Jon Trent, MD, PhD Assistant Professor Dept. of Sarcoma Medical Oncology The University of Texas, M. D. Anderson Cance

2. Background

3. GIST Overview Most common GI sarcoma 0.2% of all GI tumors, but 80% of GI sarcomas Distinct clinical and histopathologic entity Highest incidence in the 40-60 year age group Similar male/female incidence Many misclassified as leiomyosarcoma GIST have an incidence of 14.5 per million annually and a prevalence of 129 per million Clinical presentation is variable pain, hemorrhage, anemia, anorexia, nausea, perforation GIST represent a subset of sarcomas (tumors of mesenchymal origin) that develops in the gastrointestinal (GI) tract and may spread within the abdomen. GIST are relatively rare neoplasms, representing less than 1% of all tumors of the GI tract; nonetheless, GIST are the most common mesenchymal malignancy of the GI tract. The peak incidence seems to occur between 40 and 60 years of age. Men and women are affected equally, and it is unusual to find GIST in patients youngerthan 40. Approximately 4500 to 6000 cases of GIST occur annually in the United States. The prevalence of GIST is higher than its incidence, because the clinical course of the disease can last for 10 to 15 years. The definition of GIST is evolving and recently has been identified as a distinct clinical and histopathologic entity. In the past, GIST often were underdiagnosed because of confusion over classification and similarities to other tumor types.GIST represent a subset of sarcomas (tumors of mesenchymal origin) that develops in the gastrointestinal (GI) tract and may spread within the abdomen. GIST are relatively rare neoplasms, representing less than 1% of all tumors of the GI tract; nonetheless, GIST are the most common mesenchymal malignancy of the GI tract. The peak incidence seems to occur between 40 and 60 years of age. Men and women are affected equally, and it is unusual to find GIST in patients youngerthan 40. Approximately 4500 to 6000 cases of GIST occur annually in the United States. The prevalence of GIST is higher than its incidence, because the clinical course of the disease can last for 10 to 15 years. The definition of GIST is evolving and recently has been identified as a distinct clinical and histopathologic entity. In the past, GIST often were underdiagnosed because of confusion over classification and similarities to other tumor types.

4. Median Overall Survival in Metastatic GIST

5. Chemotherapy TrialsAdvanced GIST

6. GIST Overview GIST share several characteristics with ICC Neuromuscular pacemaker cell of the GI tract Found in myenteric plexus throughout GI tract Expression of CD34 in ~80% of cases Expression of KIT (CD117) in ~95% of cases It is now believed that GIST arise from mesenchymal precursor cells with the ability to differentiate into either smooth muscle or enteric neural cells, because GIST with smooth muscle or neural differentiation can each express KIT. This has led to speculation that GIST arise from cells of the enteric neural plexus, which also give rise to normal interstitial cells of Cajal (ICC). Because a subset of GIST expresses a neural phenotype, GIST now include the group of tumors previously known as GI pacemaker tumors (GIPacTs) or GI autonomic nerve tumors (GANTs). ICC are GI pacemaker cells that regulate gut peristalsis. They are important for the autonomous movement of the GI tract and require normal KIT function for their maturation, development, and survival. They develop from the gut mesenchyme, are not neural crest-derived cells, and do not express neural crest immunohistochemical markers such asS-100. ICC are uniformly KIT-positive.It is now believed that GIST arise from mesenchymal precursor cells with the ability to differentiate into either smooth muscle or enteric neural cells, because GIST with smooth muscle or neural differentiation can each express KIT. This has led to speculation that GIST arise from cells of the enteric neural plexus, which also give rise to normal interstitial cells of Cajal (ICC). Because a subset of GIST expresses a neural phenotype, GIST now include the group of tumors previously known as GI pacemaker tumors (GIPacTs) or GI autonomic nerve tumors (GANTs). ICC are GI pacemaker cells that regulate gut peristalsis. They are important for the autonomous movement of the GI tract and require normal KIT function for their maturation, development, and survival. They develop from the gut mesenchyme, are not neural crest-derived cells, and do not express neural crest immunohistochemical markers such asS-100. ICC are uniformly KIT-positive.

9. Imatinib Mesylate Rational drug design 2-phenylamino pyrimidine Based on structure of ATP binding site Highly water soluble Oral bioavailability CGP 57148 and its B salt are potent and selective inhibitors of the Bcr-Abl, v-ABL and platelet-derived growth factor (PDGF) receptor tyrosine kinases in vitro and in cells. Submicromolar concentrations of the compound selectively inhibited Abl (v-Abl and Bcr-Abl kinases) autophosphorylation and PDGF-induced receptor autophosphorylation and cellular tyrosine phosphorylation. In contrast, ligand-induced growth factor receptor autophosphorylation in response to epidermal growth factor (EGF), insulin-like growth factor-I (IGF-I), insulin and stem cell factor (KIT ligand) showed no or weak inhibition by high concentrations of CGP 57148. Furthermore, autophosphorylation of the JAK-2 kinase, which is known to be activated by interleukin-3 (IL-3) signal transduction, and FMS and SRC autophosphorylation were not affected by the compound. CGP 57148B showed potent inhibition of PDGF-induced c-fos mRNA expression, whereas c-fos mRNA expression induced by EGF, fibroblast growth factor (FGF) or phorbol ester was insensitive to inhibition by the compound. In antiproliferative assays, the compound was more than 30-fold more potent in inhibiting PDGF-mediated growth of v-sis transformed BALB/c 3T3 cells (IC50 = 0.3 mM) relative to inhibition of EGF-dependent BALB/MK cells, IL-3-dependent FDC-P1 cells and the T24 bladder carcinoma line. CGP 57148B was tested for antiproliferative activity on Bcr-Abl expressing 32D and MO7e cells and their IL-3-dependent parental cells. CGP 57148B had no effect on the proliferation of parental or v-src transformed cells at concentration up to 10 mM. In contrast, 1 mM CGP 57148 selectively killed Bcr-Abl expressing cells. CGP 57148B was tested for selective inhibition of CML colony formation using ex vivo human patient samples. The compound did not inhibit colony formation of normal bone marrow at 1 mM. In contrast, when peripheral blood or bone marrow was obtained from CML patients a 60-90% inhibition of colony formation was seen with 1 mM CGP 57148B. When colonies were assayed for the presence of Bcr-abl transcripts by PCR, less than 20% of the colonies that formed in the presence of 1 mM CGP 57148B contained Bcr-abl transcripts. Combining this data with the 60-90% inhibition of colony formation, there was an overall decrease of Bcr-abl positive colonies of 92-98%. When tested in vivo using Bcr-abl, v-abl and v-sis transformed cells, CGP 57148B showed antitumor activity at tolerated doses. Antitumor activity was also shown against the U-373 MG and U-87 MG human astrocytomas which express PDGF and PDGF receptors. In contrast, CGP 57148B had no antitumor activity when tested using v-src transformed cells. Antitumor activity against v-abl tumors was highest when compound was administered by the i.v. or i.p. routes. CGP 57148 and its B salt are potent and selective inhibitors of the Bcr-Abl, v-ABL and platelet-derived growth factor (PDGF) receptor tyrosine kinases in vitro and in cells. Submicromolar concentrations of the compound selectively inhibited Abl (v-Abl and Bcr-Abl kinases) autophosphorylation and PDGF-induced receptor autophosphorylation and cellular tyrosine phosphorylation. In contrast, ligand-induced growth factor receptor autophosphorylation in response to epidermal growth factor (EGF), insulin-like growth factor-I (IGF-I), insulin and stem cell factor (KIT ligand) showed no or weak inhibition by high concentrations of CGP 57148. Furthermore, autophosphorylation of the JAK-2 kinase, which is known to be activated by interleukin-3 (IL-3) signal transduction, and FMS and SRC autophosphorylation were not affected by the compound. CGP 57148B showed potent inhibition of PDGF-induced c-fos mRNA expression, whereas c-fos mRNA expression induced by EGF, fibroblast growth factor (FGF) or phorbol ester was insensitive to inhibition by the compound. In antiproliferative assays, the compound was more than 30-fold more potent in inhibiting PDGF-mediated growth of v-sis transformed BALB/c 3T3 cells (IC50 = 0.3 mM) relative to inhibition of EGF-dependent BALB/MK cells, IL-3-dependent FDC-P1 cells and the T24 bladder carcinoma line. CGP 57148B was tested for antiproliferative activity on Bcr-Abl expressing 32D and MO7e cells and their IL-3-dependent parental cells. CGP 57148B had no effect on the proliferation of parental or v-src transformed cells at concentration up to 10 mM. In contrast, 1 mM CGP 57148 selectively killed Bcr-Abl expressing cells. CGP 57148B was tested for selective inhibition of CML colony formation using ex vivo human patient samples. The compound did not inhibit colony formation of normal bone marrow at 1 mM. In contrast, when peripheral blood or bone marrow was obtained from CML patients a 60-90% inhibition of colony formation was seen with 1 mM CGP 57148B. When colonies were assayed for the presence of Bcr-abl transcripts by PCR, less than 20% of the colonies that formed in the presence of 1 mM CGP 57148B contained Bcr-abl transcripts. Combining this data with the 60-90% inhibition of colony formation, there was an overall decrease of Bcr-abl positive colonies of 92-98%. When tested in vivo using Bcr-abl, v-abl and v-sis transformed cells, CGP 57148B showed antitumor activity at tolerated doses. Antitumor activity was also shown against the U-373 MG and U-87 MG human astrocytomas which express PDGF and PDGF receptors. In contrast, CGP 57148B had no antitumor activity when tested using v-src transformed cells. Antitumor activity against v-abl tumors was highest when compound was administered by the i.v. or i.p. routes.

13. What is the chance of imatinib helping me?

14. Clinical Trials of Imatinib in GIST

17. EORTC Phase III Imatinib for Advanced GISTSurvival Benefit

18. How long do I take imatinib?

21. Time to Tumor Progression

22. Discontinuation of Imatinib Increases the Risk of Progression (BFR14) Patients who achieved clinical benefit after 12 months were randomized to continue or to stop imatinib mesylate therapy Randomization has been suspended Patients with unresectable or metastatic GIST (N=129) received imatinib mesylate400 mg/d for 12 months in the BFR14 trial. These patients were then randomized to either continue therapy or to stop therapy. During the first 3 months following randomization, patients were given CT scans every month for 3 months, and then every 3 months until progression. Following progression, imatinib mesylate therapy would be reinitiated. Patients on the stop therapy arm of the trial had a median PFS of 6 months following randomization, while no patients on the continue therapy arm progressed after 7 months (P=0.0001). PFS on the stop therapy arm was comparable between patients who had initially achieved a CR or PR. Following imatinib mesylate reinitiation, most patients were able to reestablish tumor control, although 1 patient who had stopped therapy has died of disease. This trial demonstrates that imatinib mesylate therapy should be continued indefinitely, even following CR. Randomization for this trial has been suspended, and all patients are eligible forimatinib therapy.Patients with unresectable or metastatic GIST (N=129) received imatinib mesylate400 mg/d for 12 months in the BFR14 trial. These patients were then randomized to either continue therapy or to stop therapy. During the first 3 months following randomization, patients were given CT scans every month for 3 months, and then every 3 months until progression. Following progression, imatinib mesylate therapy would be reinitiated. Patients on the stop therapy arm of the trial had a median PFS of 6 months following randomization, while no patients on the continue therapy arm progressed after 7 months (P=0.0001). PFS on the stop therapy arm was comparable between patients who had initially achieved a CR or PR. Following imatinib mesylate reinitiation, most patients were able to reestablish tumor control, although 1 patient who had stopped therapy has died of disease. This trial demonstrates that imatinib mesylate therapy should be continued indefinitely, even following CR. Randomization for this trial has been suspended, and all patients are eligible forimatinib therapy.

23. What dose of imatinib should I take?

24. EORTC Phase III Imatinib for Advanced GISTProgression-free Survival Benefit

25. Progression-free Survival By Imatinib Dose

26. Progression-free Survival By Imatinib Dose

27. Kit Mutation in GISTBenefit from 800mg Imatinib

28. Tell me about the side effects�..

29. Side effects: 400 vs. 800 mg

30. Interruptions and Reductions of Therapy

31. North American Intergroup Phase III Study of Imatinib in Advanced GIST

32. How do I know if imatinib is working?

33. Confirmed Overall Responses with Gleevec

35.

40. Pseudoprogression Early During Treatment With Imatinib Mesylate Pseudoprogression is uncommon, but can occur early in treatment. These images are from a 51-year-old male patient with primary GIST originating in the colon with peritoneal metastases. Although the patient appears to be progressing by anatomic criteria, 18FDG uptake was reduced by PET, and the tumor has undergone a decrease in density by CT, from 42 Hounsfield units (HU) to 30 HU.Pseudoprogression is uncommon, but can occur early in treatment. These images are from a 51-year-old male patient with primary GIST originating in the colon with peritoneal metastases. Although the patient appears to be progressing by anatomic criteria, 18FDG uptake was reduced by PET, and the tumor has undergone a decrease in density by CT, from 42 Hounsfield units (HU) to 30 HU.

41. Effects of Imatinib on GIST:CT findings

42. Modified RECIST for GISTCT Size + Density (Choi) Tumor size decrease of >10% or tumor density decrease of >15% were highly correlated with decrease in SUV by >70% to a value <2.5 on PET. RECIST criteria substantially underestimate, at least initially, the value of therapy with imatinib for GIST. _ Intratumoral hemorrage following treatment. _ max SUV vs. average HU for tumor density ODS, using tumor density, vessels, and size of solid tumor nodules in addition to the size of tumor, improved ----_ Intratumoral hemorrage following treatment. _ max SUV vs. average HU for tumor density ODS, using tumor density, vessels, and size of solid tumor nodules in addition to the size of tumor, improved ----

43. What is �genotyping?�

45. Kit Mutation in GISTResponse to Imatinib (n=332)

47. Kit-Negative GIST

48. How will you know whether my GIST comes back?

49. Type of Progression

50. Limited Progression

51. Resistance to Imatinib Mesylate: Recognition of Clonal Evolution Clonal evolution of resistance may first appear as regions of a responding tumor with increased density. In a recent study (N=89), 26% of progressing patients developed a novel progressing nodule within an existing lesion. These new nodules were the first sign of progression in 78% of these patients. Over time, these foci may form a progressing nodule with different radiodensity from the progenitor lesion.Clonal evolution of resistance may first appear as regions of a responding tumor with increased density. In a recent study (N=89), 26% of progressing patients developed a novel progressing nodule within an existing lesion. These new nodules were the first sign of progression in 78% of these patients. Over time, these foci may form a progressing nodule with different radiodensity from the progenitor lesion.

52. Secondary Mutation

53. What do I do if my GIST is resistant to imatinib?

54. Therapy by Type of Progression Limited or Nodular Progression Hepatic Artery Embolization Hepatic Radio-frequency Catheter Ablation Surgical Resection Widespread progression Increase Imatinib to 800 mg daily Sunitinib Clinical Trial

55. Hepatic Artery Embolization Hepatic artery embolization is an alternative palliative therapy for patients with tumors that cannot be resected. Embolization is performed by reducing the blood flow through the hepatic artery, which minimally affects healthy liver cells as they get their blood supply from the portal vein. Embolization may not be suitable for patients with liver diseases such as hepatitisor cirrhosis.Hepatic artery embolization is an alternative palliative therapy for patients with tumors that cannot be resected. Embolization is performed by reducing the blood flow through the hepatic artery, which minimally affects healthy liver cells as they get their blood supply from the portal vein. Embolization may not be suitable for patients with liver diseases such as hepatitisor cirrhosis.

56. Metastatic GIST Trials Phase II studies in advanced GIST AMN107: Kit and Abl inhibitor AMG 706: High affinity Kit inhibitor and VEGFR inhibitor Dasatinib: High affinity Kit, Abl and Src inhibitor (+other targets) Sorafinib: High affinity Kit inhibitor Perifosine (AKT/MapK/p21 inhibitor)+Imatinib: inhibit PI3K activation of AKT G3139 (antisense bcl-2) + Imatinib : restore apoptosis RAD0001 (mTOR inhibitor)+Imatinib Phase I studies in GISTs and other solid tumors IGF-1R inhibitor TRAIL

57. SU11248 in Advanced GISTSunitinib Malate, Sutent

58. SU11248 in Advanced GISTObjective Response Rates

59. Time to Tumor Progression

60. Should I take imatinib after my GIST was removed?

61. Survival of GIST Patients by Primary Tumor Size

62. Post-operative Imatinib Trials Z9000: ACOSOG Study of Adjuvant Imatinib in GIST Z9001: ACOSOG Randomized Study of Adjuvant Imatinib Versus Placebo in GIST Primary Objective is survival Secondary objective to obtain tumor before Imatinib and at recurrence Resected < 10 weeks prior to Imatinib High risk for local or distant failure (> 3 cm primary, intraperitoneal hemorrhage, tumor rupture) Z9002: Adjuvant Duration?

63. Preoperative Imatinib Trials MDACC ID03-0023: Preop/Postop Imatinib in Patients with Resectable GIST Laboratory correlations Clinical endpoints of DFS, OS RTOG S-0132: Preoperative Imatinib in Patients with Potentially Resectable GIST Laboratory correlations Clinical endpoints of DFS, OS Imatinib to maximum response

64. Patient Characteristicsn=13

65. Preoperative Imatinib ToxicityGrade 3/4

66. PET Response at Day 5

67. PET Response Datan=12

68. Apoptosis After Imatinib

69. Tumors were stained for CD31 (red) and TUNEL (green) and quantifed by LSC. Tumors were stained for CD31 (red) and TUNEL (green) and quantifed by LSC.

70. Will my kids get GIST?

71. Familial GIST