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GIST Overview.

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Presentation on theme: "GIST Overview."— Presentation transcript:

1 GIST Overview

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 GIST is a mesenchymal neoplasm with spindle-cell or epithelioid-cell morphology that is located primarily in the gastrointestinal (GI) tract, omentum, and mesentery. GIST usually stains positive for KIT (also known as CD117, steel factor, or stem-cell factor receptor)1 Historically, GIST was designated as a smooth muscle tumor.2 However, under electron microscopic examination, many GISTs lack typical smooth muscle or neural cell characteristics2 More recently, GISTs have been defined on the basis of 3 primary characteristics1,3,4,5 Location primarily in the GI tract, omentum, and mesentery Usually stain positive for KIT (also known as, CD117, steel factor, mast cell growth factor, or stem cell factor [SCF]) using immunohistochemical staining Presence of spindled and/or epithelioid histologic appearance compatible with GIST Most (60%-70%) GISTs occur in the stomach (50%) and small intestine (25%) and are found less commonly in the colon (10%), omentum or mesentery (7%), esophagus (5%), and other sites7 Although GIST accounts for only 0.2% of all GI tumors, it accounts for 80% of GI sarcomas Miettinen M, Lasota J. Gastrointestinal stromal tumors—review on morphology, molecular pathology, prognosis, and differential diagnosis. Arch Pathol Lab Med. 2006;130: Connolly EM, Gaffney E, Reynolds JV. Gastrointestinal stromal tumours. Br J Surg. 2003;90: Nilsson B, Bumming P, Meis-Kindblom JM, et al. Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era—a population-based study in western Sweden. Cancer. 2005;103: Goh BKP, Chow PKH, Yap W-M et al. Which is the optimal risk stratification system for surgically treated localized primary GIST? Comparison of three contemporary prognostic criteria in 171 tumors and a proposal for a modified armed forces institute of pathology risk criteria. Ann. Surg Oncol. 2008;15:: Kindblom LG, Remotti HE, Aldenborg F, Meis-Kindblom JM. Gastrointestinal pacemaker cell tumor (GIPACT): gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal. Am J Pathol. 1998;152: Fletcher C, Berman JJ, Corless C, et al. Diagnosis of gastrointestinal stromal tumors: a consesus approach. Hum Pathol. 2002;33: Demetri GD, Benjamin R, Blanke CD, et al. NCCN Task Force report: optimal management of patients with gastrointestinal stromal tumor (GIST)—expansion and update of NCCN Clinical Practice Guidelines. J Natl Compr Canc Netw. 2004;21(suppl 1):S1-S26. GI, gastrointestinal; HU, Hounsfield units. Images adapted with permission from Choi H et al. Am J Roentgenol. 2004;183: Miettinen M et al. Arch Pathol Lab Med. 2006;130:

3 GIST: Incidence An estimated 10 to 20 cases of GIST per million persons are diagnosed in the United States each year1 5000 to 6000 cases per year are diagnosed in the United States2 Incidence in Europe3-7 is estimated between 6.6 and 14.5 cases per million Highest incidence among group aged 50 to 65 years1 Similar male/female incidence, although some reports suggest higher incidence in men Prevalence in Sweden: 129 cases per million4 Historically, GIST was misdiagnosed or undiagnosed. This formerly “rare” disease is now recognized as having a much higher incidence than previously thought1 GI sarcomas were once thought to be rare.1 However, improved understanding of the pathobiology of such tumors has led to revised estimates of incidence and increased numbers of diagnoses. The estimated number of GISTs diagnosed each year in the United States is approximately cases.1 Since 1992, there has been a 50% increase in population- and age-adjusted rates of diagnosis of GI mesenchymal tumors2 European studies using a clearer definition of GIST based on the marker CD117 antigen have resulted in more accurate diagnosis of GIST. This is evident in the increase in GIST diagnoses and concurrent decrease in “GIST-like” tumor diagnoses3 Under the current, widely accepted definition of GIST, European studies and US estimates are in agreement: the incidence of GIST is in the range of 7-20 cases per million3-8 The highest incidence of GIST occurs in patients aged years. Although some studies indicate a higher incidence among men, others show an equal distribution between men and women4 In one study in Sweden, the prevalence of GIST was estimated at 129 cases per million5 Fletcher CDM, Berman JJ, Corless C, et al. Diagnosis of gastrointestinal stromal tumors: a consensus approach. Hum Pathol. 2002;33: Perez EA, Livingstone AS, Franceschi D, et al. Current incidence and outcomes of gastrointestinal mesenchymal tumors including gastrointestinal stromal tumors. J Am Coll Surg. 2006;202: Goettsch WG, Bos SD, Breekveldt-Postma N, et al. Incidence of gastrointestinal stromal tumours is underestimated: results of a nation-wide study. Eur J Cancer. 2005;41: Miettinen M, Lasota J. Gastrointestinal stromal tumors—definition, clinical, histological, immunohistochemical, and molecular genetic features and differential diagnosis. Virchows Arch. 2001;438:1-12. Nilsson B, Bumming P, Meis-Kindblom JM, et al. Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era—a population-based study in western Sweden. Cancer. 2005;103: Tryggvason G, Gislason HG, Magnusson MK, Jonasson JG. Gastrointestinal stromal tumors in Iceland, : the Icelandic GIST study, a population-based incidence and pathologic risk stratification study. Int J Cancer. 2005;117: Rubio J, Marcos-Gragera R, Ortiz MR, et al. Population-based incidence and survival of gastrointestinal stromal tumours (GIST) in Girona, Spain. Eur J Cancer. 2007;43: Mucciarini C, Rossi G, Bertolini F, et al. Incidence and clinicopathologic features of gastrointestinal stromal tumors. A population-based study. BMC Cancer. 2007;7:230. 1. Miettinen M et al. Virchows Arch. 2001;438:1-12. 2. Fletcher CDM et al. Hum Pathol. 2002;33: 3. Goettsch WG et al. Eur J Cancer. 2005;41: 4. Nilsson B et al. Cancer. 2005;103: 5. Tryggvason G et al. Int J Cancer. 2005;117: 6. Rubio J et al. Eur J Cancer. 2007;43: 7. Mucciarini C et al. BMC Cancer. 2007;7:230.

4 GIST: Clinical Presentation
Symptoms of GIST at Diagnosis1 Symptom Occurrence Rate Abdominal pain 50%-70% GI bleeding 50% Most patients present with nausea, vomiting, pain, weight loss, palpable tumor masses, and bleeding leading to anemia2 Average duration of presenting symptoms is 4 to 6 months2 Patients with GIST present with a range of symptoms associated with the location of the disease; about half have abdominal pain and GI bleeding Vague GI pain or discomfort and GI bleeding are the most frequent presenting symptom, with an incidence of 50%-70% and 50%, respectively1 Most patients present with nausea, vomiting, pain, weight loss, palpable tumor masses, and bleeding that leads to anemia. The average duration of presenting symptoms is 4-6 months2 Often, many small GISTs are discovered during endoscopy or laproscopy performed for other reasons. Upon presentation, 15%-50% of GISTs are overtly metastatic3 Unlike leiomyosarcomas of the GI tract or abdomen, GISTs typically do not metastasize to pulmonary tissue; they typically metastasize to the peritoneum and the liver3 Miettinen M, Sarlomo-Rikala M, Lasota J. Gastrointestinal stromal tumors: recent advances in understanding of their biology. Hum Pathol. 1999;30: Ghanem N, Altehoefer C, Furtwangler A, et al. Computed tomography in gastrointestinal stromal tumors. Eur Radiol. 2003;13: Joensuu H, Fletcher C, Dimitrijevic S, et al. Management of gastrointestinal stromal tumors. Lancet Oncol. 2002;3: 1. Miettinen M et al. Hum Pathol. 1999;30: 2. Ghanem N et al. Eur Radiol. 2003;13:

5 Circumstances of GIST Detection
Approximately one-third of GISTs are asymptomatic1,2 Incidental Symptomatic Autopsy 69% 21% 10% Nearly one-third of GISTs located in the stomach and small intestines are asymptomatic1,2 Even in symptomatic GIST, symptoms are often vague and nonspecific, including vague GI pain or discomfort, nausea, and fatigue2,3 Kindblom LG. Gastrointestinal stromal tumors: diagnosis, epidemiology, prognosis. Accessed October 23, 2006. Miettinen M, Sarlomo-Rikala M, Lasota J. Gastrointestinal stromal tumors: recent advances in understanding of their biology. Hum Pathol. 1999;30: Connolly EM, Gaffney E, Reynolds JV. Gastrointestinal stromal tumours. Br J Surg. 2003;90: Kindblom LG. vgnextoid=8a7ca1f VgnVCM100000f2730ad1RCRD&spk=Kindblom%2C+Lars-Gunnar+%5Bfau%5D. Miettinen M et al. Hum Pathol. 1999;30:

6 Common Tumor Sites GIST may arise anywhere along the GI tract or elsewhere in the abdomen or retroperitoneum1 Colon, rectum, esophagus, mesentery, omentum 15% Stomach GIST may occur anywhere along the GI tract, from the esophagus to the rectum, but the most common sites include the stomach (60%) and the small intestine (25%)1 Almost two-thirds of GISTs are malignant. Size and mitotic rate are the most useful morphologic features in predicting malignant behavior2 The metastatic pattern is predominantly intra-abdominal, with spread throughout the peritoneal cavity and to the liver. Lymph node invasion is uncommon3 True smooth-muscle tumors (ie, leiomyomas) also occur throughout the GI tract but are now thought to be rare in comparison with GIST, except in the esophagus, where they are more common4 Corless CL, Heinrich MC. Molecular pathobiology of gastrointestinal stromal sarcomas. Annu Rev Pathol. 2008;3: Pidhorecky I, Cheney RT, Kraybill WG, Gibbs JF. Gastrointestinal stromal tumors: current diagnosis, biologic behavior, and management. Ann Surg Oncol. 2000;7: Miettinen M, Majidi M, Lasota J. Pathology and diagnostic criteria of gastrointestinal stromal tumors (GISTs): a review. Eur J Cancer. 2002;38(suppl 5):S39-S51. Hatch KF, Blanchard DK, Hatch GF, et al. Tumors of the rectum and anal canal. World J Surg. 2000;24: 60% Small intestine 25% 1. Corless CL et al. Annu Rev Pathol. 2008;3:

7 KIT and PDGFRa Receptor Structures
Type 3 receptor tyrosine kinases Extracellular domain binds ligand SCF for KIT PDGF for PDGFR Downstream effects of ligand binding to KIT or PDGR are proliferative and antiapoptotic Intracellular domain has 2 tyrosine kinase domains Multiple autophosphorylation sites SCF or PDGF binding site 5 IgG domains Cell membrane KIT and PDGFR function as a transmembrane tyrosine kinase receptors. Their structure is homologous to another protein tyrosine kinases: BCR-ABL tyrosine kinase1,2 The KIT and PDGFR receptors have 5 Ig-like extracellular domains and an intracellular split tyrosine kinase domain1 The physiologic ligand to KIT is the cytokine stem cell factor (SCF)1, while the physiologic ligand to PDGFR is the platelet derived growth factor (PDGF)2 KIT and PDGFR genes are localized to chromosome 4q11-q123 Taylor ML, Metcalfe DD. Kit signal transduction. Hematol Oncol Clin North Am. 2000;14: Corless CL, Heinrich MC. Molecular pathobiology of gastrointestinal stromal sarcomas. Annu Rev Pathol. 2008;3: d'Auriol L, Mattei MG, Andre C, Galibert F. Localization of the human c-kit protooncogene on the q11-q12 region of chromosome 4. Hum Genet. 1988;78: Tyrosine kinase domains SCF, stem cell factor; PDGF, platelet-derived growth factor; IgG, immunoglobulin G. 1. Taylor ML et al. Hematol Oncol Clin North Am. 2000;14: 2. Corless CLet al. Annu Rev Pathol. 2008;3:

8 Normal KIT Signaling Kinase domains P P ADP P ATP P P P
A substrate protein (eg, PI3 kinase) is phosphorylated by KIT kinase1,2 Substrate Kinase domains Effector P P ADP Activation of the substrate initiates a signaling cascade, culminating in cell proliferation and survival1,2 Normal KIT signaling involves phosphorylation of a substrate protein and activation of signal-transduction pathways, which play an essential role in cell growth, differentiation, and apoptosis1,2 KIT signaling begins when ATP binds to the membrane-proximal kinase domain of KIT1 This allows the substrate to be phosphorylated1 Following phosphate transfer, the phosphosubstrate is able to bind to and activate downstream effector molecules1 Savage DG, Antman KH. Imatinib mesylate—a new oral targeted therapy. N Engl J Med. 2002;346: Scheijen B, Griffin JD. Tyrosine kinase oncogenes in normal hematopoiesis and hematological disease. Oncogene. 2002;21: P ATP P P P SIGNALING ADP, adenosine diphosphate. 1. Savage DG et al. N Engl J Med. 2002;346: 2. Scheijen B et al. Oncogene. 2002;21:

9 Normal Biologic Function of KIT Receptor Tyrosine Kinase
KIT plays an essential role1,2 in Activation of KIT is critical in cell functions, including1 Hematopoiesis Proliferation Skin pigment Differentiation Fertility Apoptosis/survival Gut motility (pacemaker cells) Adhesion/chemotaxis The KIT receptor tyrosine kinase plays an important role in normal biologic functions; however, gain-of-function mutations in KIT can lead to the development of GIST1-3 In normal tissue, the receptor tyrosine kinase KIT and its ligand, SCF, are essential for1 Hematopoiesis Melanogenesis Fertility and gametogenesis Gut motility KIT signal transduction has been shown to play a pivotal role in various cell functions, including proliferation, differentiation, apoptosis and survival, adhesion, and possibly chemotaxis1 However, gain-of-function mutations in KIT result in the expression of a KIT protein with deregulated (ligand-independent) activity, which can lead to the development of GIST1 Familial gain-of-function KIT mutations have been shown to result in high incidence of GIST, melanocytic dysfunction, and cutaneous mastocytosis2 Taylor ML, Metcalfe DD. Kit signal transduction. Hematol Oncol Clin North Am. 2000;14: Beghini A, Tibiletti MG, Roversi G, et al. Germline mutation in the juxtamembrane domain of the kit gene in a family with gastrointestinal stromal tumors and urticaria pigmentosa. Cancer. 2001;92: Hirota S, Isozaki K, Moriyama Y, et al. Gain-of function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998;279: 1. Taylor ML et al. Hematol Oncol Clin North Am. 2000;14: 2. Beghini A et al. Cancer. 2001;92:

10 KIT Mutations Up to 95% GISTs stained positive for KIT1
A subset (2% to 5%) of GIST stain negative for KIT expression2 Mutant forms of KIT are constitutively active3 Knock-in mice studies with KIT mutations showed4 Constitutive KIT signaling is sufficient to induce GIST Parallel pathology is seen with familial KIT mutations (eg, mastocytosis) Microscopic GISTs are thought to be common in the general population5-7 Some micro-GISTs harbor mutations in KIT or PDGFRA genes Genetic events that transform these micro-GISTs into clinically important disease are not well understood Up to 95% of GIST samples have mutations in the KIT gene, although a subset (2% to 5%) of GIST stain negative for KIT expression1,2 In a seminal paper published in the journal Science in 1998, Hirota et al evaluated KIT expression in 58 mesenchymal tumors from the GI wall and found that the only GI wall–resident cells to also express these markers were ICC3 Hirota et al sequenced cDNA derived from 6 GISTs and determined that 5 of these 6 GISTs had a mutant KIT allele, with the mutation being manifested in the juxtamembrane (cytosolic) region of the KIT protein3 These mutations were found to constitutively activate KIT signaling. If such a mutant KIT allele were transfected into IL-3/SCF–dependent cell lines, the transformed line was able to grow autonomously, ie, without IL-3/SCF3 Based on these data, Hirota et al proposed that GIST may arise from ICC3 In mice with the KITv558 mutation, heterozygotes develop GI hyperplasia similar to GIST. Additionally, as with familial GIST, master cell numbers are increased in the skin of these mice4 Results from recent studies suggest that there is a large pool of microscopic GISTs (maximum lesion size, 10 mm) in the general population.5-7 Micro-GISTs were found during autopsy in the stomachs of 23% of adults aged >50 years,5 in 35% of patients with gastric cancer,6 and in 10% of patients with esophageal or esophagogastric junction carcinomas7 Mutations in KIT and PDGFRA genes have been detected in some micro-GISTs. However, because the majority of these micro-GISTs do not progress to clinically significant disease, a series of genetic events, still not well understood, appears to be necessary to induce full-blown GIST4,5 Corless CL, Heinrich MC. Molecular pathobiology of gastrointestinal stromal sarcomas. Annu Rev Pathol. 2008;3: Heinrich CM, Owzar K, Corles CL, et al. Correlation of kinase genotype and clinical outcome in the North American Inter-Group phase III trial of imatinib mesylate for treatment of advanced GI stromal tumor (CALGB ). J Clin Oncol In press. Hirota S, Isozaki K, Moriyama Y, et al. Gain-of function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998;279: Sommer G, Agosti V, Ehlers I, et al. Gastrointestinal stromal tumors in a mouse model by targeted mutation of the Kit receptor tyrosine kinase. Proc Natl Acad Sci U S A. 2003;100: Agaimy A, Wunsch PH, Hofstaedter F, et al. Minute gastric sclerosing stromal tumors (GIST tumorlets) are common in adults and frequently show c-KIT mutations. Am J Surg Pathol. 2007;31: Kawanowa K, Sakuma Y, Sakurai S, et al. High incidence of microscopic gastrointestinal stromal tumors in the stomach. Hum Pathol. 2006;37: Abraham SC, Krasinskas AM, Hofstetter WL, Swisher SG, Wu TT. "Seedling" mesenchymal tumors (gastrointestinal stromal tumors and leiomyomas) are common incidental tumors of the esophagogastric junction. Am J Surg Pathol. 2007;31: 1. Corless CL et al. Annu Rev Pathol. 2008;3: 2. Heinrich CM et al. J Clin Oncol. In press. 3. Hirota S et al. Science. 1998;279: 4. Sommer G et al. Proc Natl Acad Sci U S A. 2003;100: 5. Agaimy A et al. Am J Surg Pathol. 2007;31: 6. Kawanowa K et al. Hum Pathol. 2006;37: 7. Abraham SC et al. Am J Surg Pathol. 2007;31:

11 Histopathology GISTs range in size from 1 to 40 cm (average ~5 cm)2
Spindle cell Epithelioid cell Mixed morphology1 GISTs range in size from 1 to 40 cm (average ~5 cm)2 GIST can be classified into 3 broad categories1 Spindle-cell type (70%) Epithelioid-cell type (20%) Mixed spindle-cell and epithelioid-cell type (nested morphology) (10%) GISTs generally range in size from 1 to 40 cm (average ~5 cm) and have spindle- cell (70%), epithelioid-cell (20%), or mixed spindle-epithelioid (10%) histomorphology1,2 On diagnosis, GIST generally is 1-40 cm in size. Tumor size is a factor when determining disease aggressiveness and prognosis1 Histologically, GIST can be classified into 3 broad categories: spindle-cell type (70%), epithelioid-cell type (20%), and mixed spindle-cell and epithelioid-cell type (mixed morphology) (10%)2 GIST has a remarkably uniform appearance, with only a small minority having a notable cytologic pleomorphism (<2%-3%)2 Corless CL, Heinrich MC. Molecular pathobiology of gastrointestinal stromal sarcomas. Annu Rev Pathol. 2008;3: Fletcher CD, Berman JJ, Corless C, et al. Diagnosis of gastrointestinal stromal tumors: a consensus approach. Hum Pathol. 2002;33: Fletcher CD et al. Hum Pathol. 2002;33: Corless CL et al. Annu Rev Pathol. 2008;3:

12 Imatinib Treatment for Unresectable or Metastatic GIST

13 Algorithm: Imatinib Treatment in Unresectable or Metastatic GIST1,2
Metastatic KIT exon 9+ Imatinib 800 mg/d Metastatic Imatinib 400 mg/d Unresectable Imatinib 400 mg/d OR or SD Continue imatinib Progression OR or SD Dose-escalate Imatinib 800 mg/d Secondary surgery Continue imatinib Progression OR or SD Continue imatinib Limited/Local Generalized/ Systemic Evidence-based recommendations for the treatment of unresectable and/or metastatic GIST support the optimization of imatinib dosing in progressive disease and in KIT exon 9–positive metastatic disease1-3 For a patient with metastatic and/or resectable GIST, imatinib should be initiated at a dose of 400 mg/d. Available data do not show consistent differences in overall survival (OS) between 400 mg/d and 800 mg/d (400 mg BID) in unselected patients3 A starting dose of 800 mg/d is appropriate for patients with documented KIT exon 9 mutations3 Dose escalation to 800 mg/d may be appropriate in patients who have disease progression on imatinib therapy3 If local progression occurs in a patient receiving imatinib 800 mg/d, imatinib should be continued along with local treatment (eg, surgery, radiofrequency ablation [RFA])3 If multifocal resistance occurs with generalized progression after escalation to 800 mg/d, a second-line KIT/PDGFR inhibitor (sunitinib) or an investigational second-line or third-line agent should be considered3 In patients with progressive disease, careful monitoring of therapeutic effect using CT or PET is important so the approach to management can be adjusted as appropriate3 Reichardt P. Optimising therapy for GIST. EJC Suppl. 2006;4(suppl 1):19-26. National Comprehensive Cancer Network. Clinical practice guidelines in oncology. Soft tissue sarcoma. V nccn.org. Demetri GD, Benjamin RS, Blanke CD, et al. NCCN Task Force report: management of patients with gastrointestinal stromal tumor (GIST)—update of the NCCN Clinical Practice Guidelines. J Natl Compr Canc Netw. 2007;5(suppl 2):S1-29. Continue imatinib at same dose or Increase imatinib dose as tolerated or Switch to alternate TKI Consider surgery, RFA Increase imatinib dose as tolerated or Change to sunitinib Consider clinical trial (eg, nilotinib) OR, overall response; RFA, radiofrequency ablation; SD, stable disease. 1. Reichardt P. EJC Suppl. 2006;4(suppl 1):19-26. 2. NCCN. Clinical practice guidelines. Soft tissue sarcoma. V 3. Demetri GD et al. J Natl Compr Canc Netw. 2007;5(suppl 2):S1-S29.

14 Imatinib in GIST: Rationale
As a specific inhibitor of tyrosine kinase activity, imatinib blocks kinase-mediated downstream signaling1 Mutations ~90% of GIST harbor mutations in KIT or PDGFRA genes2 Mutations occur early in the development of GIST1,2 Incidental tumors 1 cm have KIT mutations Germ-line KIT mutations are associated with multiple GISTs Cytogenetic changes in GIST are preceded by KIT mutations Hypothesis Use of imatinib to selectively inhibit KIT and PDGFRA receptor tyrosine kinases will be effective in the treatment of GIST1 The rationale for the use of imatinib in GIST is founded on the fact that oncogenic mutations of KIT or PDGFRA are essential to the development of most GISTs and imatinib is a potent and selective inhibitor of these kinases1,2 Approximately 90% of GISTs have an oncogenic mutation of KIT or PDGFRA, which occurs early in GIST development and is required for GIST cell growth and survival1,3 KIT mutations are detectable in incidental tumors 1 cm Patients with germline KIT mutations develop multiple GISTs KIT mutations precede cytogenetic changes in GIST development Imatinib is a specific inhibitor of KIT tyrosine kinase activity. Inhibiting KIT tyrosine kinase activity blocks KIT-mediated downstream signal transduction pathways2 Based on these observations, it was hypothesized that, similar to CML, the selective inhibition of KIT and PDGFR receptor tyrosine kinases with imatinib would be effective for treating GIST Heinrich MC, Rubin BP, Longley BJ, Fletcher JA. Biology and genetic aspects of gastrointestinal stromal tumors: KIT activation and cytogenetic alterations. Hum Pathol. 2002;33: Manley PW, Cowan-Jacob SW, Buchdunger E, et al. Imatinib: a selective tyrosine kinase inhibitor. Eur J Cancer. 2002;38(suppl 5):S19-S27. Heinrich MC, Corless CL, Duensing A, et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science. 2003;299: 1. Manley PW et al. Eur J Cancer. 2002;38(suppl 5):S19-S27. 2. Heinrich MC et al. Hum Pathol. 2002;33:

15 Inhibition of KIT Signaling by Imatinib
The ATP binding pocket of the KIT kinase domain is occupied by imatinib1 Substrate phosphorylation is prevented and signaling is inhibited1 With signaling inhibited, proliferation and survival are interrupted1,2 Kinase domains At the molecular level, imatinib targets a specific part of the tyrosine kinase region in KIT, BCR-ABL, and PDGFR and PDGFRβ, preventing phosphorylation and interrupting proliferation and survival signaling pathways within the cell1,2 Imatinib is an ATP-mimetic agent that binds to the ATP binding site of KIT with greater affinity than ATP1 The tyrosine kinase activity of KIT is dependent on its ATP activity1 This competitive blockade by imatinib prevents ATP binding and hydrolysis and thereby inhibits the tyrosine kinase action of KIT1 Savage DG, Antman KH. Imatinib mesylate—a new oral targeted therapy. N Engl J Med. 2002;346: Scheijen B, Griffin JD. Tyrosine kinase oncogenes in normal hematopoiesis and hematological disease. Oncogene. 2002;21: P ATP Imatinib mesylate SIGNALING 1. Savage DG et al. N Engl J Med. 2002;346: 2. Scheijen B et al. Oncogene. 2002;21:

16 Pivotal Phase 2 Trial: Design
Imaging was performed with CT scanning or MRI PET imaging was performed at the discretion of the investigator Imatinib (400 mg/d) Metastatic or unresectable GIST (N = 147) Continue to treat as long as patient benefits and drug-related safety concerns are absent PD In this open-label phase 2 study, 147 patients with metastatic and/or unresectable GIST were randomized to imatinib 400 mg/d or 600 mg/d1 A total of 147 patients were randomized into 2 groups, receiving imatinib at either 400 or 600 mg/d Crossover from the 400-mg to the 600-mg treatment arm was possible if disease progression occurred Imaging was performed with CT scanning or MRI. PET scan imaging was performed at the discretion of the investigator Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med. 2002;347: Imatinib (600 mg/d) CT, computed tomography; MRI, magnetic resonance imaging. Demetri GD et al. N Engl J Med. 2002;347:

17 Pivotal Phase 2 Trial: Best Observed Rates of Response to Imatinib
Based on Slide 53 from IM TX deck Tumor Control 400 mg/d (n = 73) 600 mg/d (n = 74) Follow-up results at 5 years from the B2222 phase 2 study of imatinib in advanced GIST showed high rates of durable disease control and clinical benefits (objective response and stable disease) At median follow-up of 63 months, rates of best observed response were partial response (PR) 69% for the 400 mg/d group and 65% (including 3 complete responses) for the 600 mg/d group Throughout long-term follow-up, approximately 85% of patients experienced clinical benefit from imatinib in the form of an objective tumor response or stable disease. In this trial, responses were defined using the size-based Southwest Oncology Group (SWOG) criteria Blanke CD, Demetri GD, von Mehren M, et al. Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol. 2008;26: CR PR SD CR PR SD 63 Months’ Median Follow-up2 CR, complete response. Blanke CD et al. J Clin Oncol. 2008;26:

18 B2222 Study (63 Months’ Median Follow-up)
Pivotal Phase 2 Trial: Kaplan-Meier Estimate of OS Since Start of Study by Best Response B2222 Study (63 Months’ Median Follow-up) Achievement of either objective tumor response or stable disease with imatinib resulted in similarly prolonged survival The median time to treatment failure in the responders was 122 weeks (28.2 months), and the median time to treatment failure for the overall population was 84 weeks (19.4 months)1 OS of patients with progressive disease (PD) was 36 weeks (8.3 months)1 For patients with stable disease (SD) (defined using SWOG criteria), median overall survival (OS) was not reached at 252 weeks. Patients with a PR experienced a median OS of 248 weeks (57.2 months)1,2 Historical results have reported a median OS of 65 weeks (15 months) in patients with GIST who receive chemotherapy instead of imatinib3 Blanke CD, Demetri GD, von Mehren M, et al. Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol. 2008;26: Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med. 2002;347: Mudan SS, Conlon KC, Woodruff JM et al. Salvage Surgery for Patients with recurrent Gastrointestinal Sarcoma: prognostic factors to guide patient selection. Cancer Jan 1;88(1):66-74. CI, confidence interval; LL, lower limit; N/A, not available; UL, upper limit. Adapted with permission of Blanke CD et al. J Clin Oncol. 2008;26:

19 Pivotal Phase 2 Trial: Summary
147 patients randomized to 400 or 600 mg/d1 At 5-year follow-up, 84% of patients showed clinical benefit2 68% PR or CR 16% SD Median TTP was 2 years2 The median OS was 4.8 years (57 months) Similar OS in patients with PR and SD suggests similar clinical benefit across SWOG categories Although low tumor bulk predicted improved OS, a substantial proportion of patients with highest tumor bulk remained alive at 64 months of follow-up3 Maintenance of imatinib plasma trough levels (Cmin) above 1110 ng/ mL is associated with best rates of clinical benefit and longest TTP4 Results indicate that imatinib is highly active and results in durable, long-term responses in patients with KIT-positive unresectable and/or metastatic GIST1,2 At more than 5 years of follow-up (median, 63 months), 84% of patients showed a clinical benefit from imatinib, with 68% achieving PR or CR and 16% SD2 Median TTP was 2 years2 The median OS was 4.8 years (57 months). Rates of OS were similar in patients with PR and SD, suggesting similar clinical benefit across these SWOG categories2 At 64 months, although patients with the lowest tumor bulk had improved survival over those with the highest tumor bulk, a substantial proportion of patients with the highest tumor bulk remained alive3 Maintenance of imatinib plasma trough levels (Cmin) above 1110 ng/mL is associated with best rates of clinical benefit and longest TTP4 Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med. 2002;347: Blanke CD, Demetri GD, von Mehren M, et al. Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol. 2008;26: Blanke C, Demetri GD, von Mehren M, et al. Efficacy of imatinib mesylate in advanced gastrointestinal stromal tumor (GIST) patients according to tumor bulk. Poster presented at: 2007 ASCO Gastrointestinal Cancers Symposium; January 19-21, 2007; Orlando, FL. Abstract 21. Demetri GD, Wang Y, Wehrle E, Blanke C, Joensuu H, von Mehren M. Correlation of imatinib plasma levels with clinical benefit in patients (Pts) with unresectable/metastatic gastrointestinal stromal tumors (GIST) [ASCO abstract 3]. Presented at: 2008 Gastrointestinal Cancers Symposium; January 25-27, 2008; Orlando, FL. SWOG, Southwest Oncology Group; TTP, time to progression. 1. Demetri GD et al. N Engl J Med. 2002;347: 2. Blanke CD et al. J Clin Oncol. 2008;26: 3. Blanke C et al. ASCO Gastrointestinal Cancers Symposium; Abstract 21. 4. Demetri GD et al. ASCO Gastrointestinal Cancers Symposium; Abstract 3.

20 Phase 3 Trials: Design EORTC/ISG/AGITG Study 620051
North American Intergroup Study S00332 Imatinib (400 mg/d) Metastatic or unresectable GIST Follow for PFS PD In both phase 3 studies, patients with metastatic or unresectable GIST were randomized into 2 imatinib treatment groups1,2 Patients were randomized to receive imatinib at either 400 or 800 mg/d1,2 Crossover from the 400-mg to the 800-mg treatment arm was possible if disease progression occurred1,2 Patients were followed to evaluate the effect of 2 different doses of imatinib on PFS1,2 Blanke CD, Rankin C, Demetri GD, et al. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the Kit receptor tyrosine kinase: S0033. J Clin Oncol. 2008;26: Verweij J, Casali PG, Zalcberg J, et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet. 2004;364: Imatinib (800 mg/d) 1. Verweij J et al. Lancet. 2004;364: 2. Blanke CD et al. J Clin Oncol. 2008;26:

21 EORTC 62005 Studies and Intergroup S0033: PFS (Primary End Point)
EORTC Study1 (N = 946) North American Intergroup S0033 Study2 (N = 694) In the Phase 3 EORTC study, patients who received the 800 mg/d starting dose had significantly improved 2-year PFS, compared with patients started on 400 mg/d1; however, in the phase 3 Intergroup S0033 study, PFS at 40 months’ follow-up did not differ between the 400-mg/d and 800-mg/d treatment groups2 This figure shows PFS by treatment group in the phase 3 EORTC (left graph)1 and in the Phase 3 Intergroup S0033 study (right graph)2 EORTC At 2 years of follow-up (median, 760 days), 263 (56%) patients allocated to imatinib 400 mg/d had progression, compared with 235 (50%) who were assigned to 800-mg/d treatment (estimated hazard ratio 0.82 [95% confidence interval [CI], ], P = 0.026)1 At median follow-up of 40 months, the difference in PFS between the 2 doses was no longer statistically significant; median PFS was 22 months3 PFS did not differ between complete and partial responders1 S0033 study2 With median follow-up of 4.5 years in study S0033, PFS did not differ significantly between the 400-mg/d and 800-mg/d imatinib dosing arms (2-sided P = 0.13) Of the 345 eligible patients randomly assigned to treatment with 400 mg/d, 278 progressed or died; their median PFS was 18 months (95% CI, months), and their 2-year PFS rate was 41% (95% CI, 36%-47%) A total of 267 of 349 eligible patients randomly assigned to treatment with high-dose imatinib progressed or died. PFS in this group was 20 months (95% CI, months), and 2-year PFS was 46% (95% CI, 41%-51%) Verweij J, Casali PG, Zalcberg J, et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet. 2004;364: Blanke CD, Rankin C, Demetri GD, et al. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the Kit receptor tyrosine kinase: S0033. J Clin Oncol. 2008;26: Casali PG, Verweij J, Zalcberg J, et al. Imatinib mesylate in advanced gastrointestinal stromal tumors (GIST): survival analysis of the intergroup EORTC/ISG/AGITG randomized trial in 946 patients [ECCO abstract 711]. Presented at: 13th European Cancer Conference. October 30-November 3, 2005; Paris, France. Adapted with permission from Blanke CD et al. J Clin Oncol. 2008;26: Adapted with permission from Verweij J et al. Lancet. 2004;364: 1. Verweij J et al. Lancet. 2004;364: 2. Blanke CD et al. J Clin Oncol. 2008;26:

22 MetaGIST: Overall PFS Advantage Among Patients Treated With Imatinib 800 mg/d in Phase 3 Trials
45-Month Follow-up Median PFS, years 3 Years Estimated (Kaplan-Meier) 400 mg/d 800 mg/d HR P value PFS All patients (N = 1640) 1.58 1.95 30% 34% 0.89 0.041 EORTC (N = 946) 1.74 2.02 31% 35% 0.12 SWOG (N = 649) 1.46 1.64 29% 33% 0.18 OS (N = 1640) 4.08 4.05 60% 61% 1.00 0.97 PFS According to KIT Exon 9 Mutation Status All patients (N = 91) 0.5 1.59 5% 17% 0.58 0.017 EORTC (N = 59) 0.35 1.62 0% 25% 0.43 0.0023 SWOG 0033 (N = 32) 0.78 1.4 14% 6% 0.99 A meta-analysis of both studies, based on results for 1640 patients, showed a significant PFS advantage for 800-mg initial daily dosing, particularly in patients with a KIT exon 9 mutation With a median follow-up of 45 months, a meta-analysis of data from both of the phase 3 studies showed a small but significant PFS advantage for imatinib 800 mg/d over 400 mg/d (P = 0.041). However, OS was the same for the 2 doses The study also examined whether mutational status might predict response to high-dose versus low-dose imatinib. In patients across the 2 studies who had KIT exon 9 mutations, high-dose imatinib resulted in a significant advantage in PFS (P = 0.017). Again, there was no difference in OS between the 2 starting doses among patients with KIT exon 9 mutations The evidence suggests that the relative benefit of imatinib 800-mg initial daily dosing may depend on the GIST mutational status Poor performance status, high baseline absolute neutrophil count (ANC), absence of KIT exon 11 mutations, and male sex adversely affected both PFS and OS, independently of the daily dose Van Glabbeke MM, Owzar K, Rankin C, Simes J, Crowley J. Comparison of the two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors (GIST): a meta-analysis based on 1,640 patients (pts) [ASCO abstract 10004]. J Clin Oncol. 2007;25(18S):546s. Adapted with permission from Van Glabbeke MM et al. J Clin Oncol. 2007;25(18S):546s. Abstract

23 Monitoring GIST and Assessing Response to Treatment

24 CT Imaging of Advanced Disease
CT should be used to evaluate the extent of advanced GIST GIST metastases are most often found in the liver and peritoneal cavity and rarely in the bone, pleura, soft tissue, and lungs Unlike adenocarcinoma of the bowel, GIST rarely infiltrates into adjacent organs or structures and almost never metastasizes to the regional nodes Demetri GD, Benjamin R, Blanke CD, et al. NCCN Task Force report: optimal management of patients with gastrointestinal stromal tumor (GIST)—expansion and update of NCCN Clinical Practice Guidelines. J Natl Compr Canc Netw. 2004;21(suppl 1):S1-S26. Hepatic metastasis ( ) Hyperdense or rim-enhancing lesions Hepatic metastasis and peritoneal implants ( ) Hyperdense masses filled with enhancing tumor nodules or nodules at the periphery Notice small tumor vessels ( ) Peritoneal implants and a subcutaneous mass ( ) Multiple hyperdense enhancing masses Images courtesy of H. Choi.

25 18FDG-PET Imaging Large hepatic metastasis
In patients with GIST, 18FDG-PET provides a highly sensitive assessment of tumor location and metabolic activity1 The ability of 18FDG-PET to evaluate tumor location and metabolic activity is useful in identifying metastases in patients presenting with recurrent or metastatic GIST Van den Abbeele AD, Badawi RD. Use of positron emission tomography in oncology and its potential role to assess response to imatinib mesylate therapy in gastrointestinal stromal tumors (GISTs). Eur J Cancer. 2002;38(suppl 5):S60-S65. Large hepatic metastasis Hepatic, abdominal, and pelvic metastases Images courtesy A.D. Van den Abbeele.

26 Limitations of Conventional Response (RECIST/SWOG) Evaluation in GIST
Tumor shrinkage may evolve slowly Focal progressive lesions may develop, even with decrease in tumor bulk1 Fluid expansion in responding necrotic GIST may result in increase in tumor size1 Criteria do not capture change in tumor density1 Criteria underestimate overall clinical benefit by not including stable disease in the evaluation1,2 Survival of patients with stable disease similar to that of patients with objective response (Study B2222)3 RECIST are limited in assessing response to imatinib in GIST and may underestimate overall clinical benefit of imatinib in such tumors1,2 In general, when GISTs respond to imatinib, there is a decrease in tumor size. However, changes in tumor size do not always correlate with response, and size may increase because of expansion of fluid in responding necrotic tumors1 Appearance of focal progressive lesions, regardless of change in tumor size, may occur in GISTs responding to imatinib1 Results from several studies suggest that size-based criteria underestimate overall clinical benefit from imatinib1,2 The phase 2, open-label, randomized B2222 study used the SWOG criteria to measure objective response. At 5 years, there was no significant difference in survival between patients with stable disease (SD) and those with PR, indicating a potential lack of sensitivity in response criteria3 Choi H. Critical issues in response evaluation on computed tomography: lessons from the gastrointestinal stromal tumor model. Curr Oncol Rep. 2005;7: LeCesne A, Van Glabbeke M, Verweij J, et al. Is a stable disease according to RECIST criteria a real stable disease in GIST patients treated with imatinib mesylate (IM) included in the intergroup EORTC/ISG/AGITG trial? [ASCO abstract 9510]. J Clin Oncol. 2006;24(suppl):522s. 3. Blanke CD, Demetri GD, von Mehren M, et al. Long-term results from a randomized Phase II trial of standard versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol. 2008;26: Choi H. Curr Oncol Rep. 2005;7: LeCesne A et al. J Clin Oncol. 2006;24(suppl):522s. Abstract 9510. 3. Blanke CD et al. J Clin Oncol. 2008;26:

27 RECIST Did Not Predict Outcome in a Phase 3 Imatinib Trial (62005)
2 Months (n = 852) 4 Months (n = 681) 6 Months (n = 642) Category TTP (y) 3-Year OS (%) CR/MR/PR responders 2.43 69.7 2.52 71.8 2.54 71 NC+/NC– 1.73 53.6 1.8 56.3 2.04 70.9 PD nonresponders 0.15 13.6 0.31 25.6 0.48 19.7 With respect to time to tumor progression (TTP) and 3-year OS, a >10% reduction in tumor load in study showed that no tumor change (SD) was equivalent to objective response1 After 6 months of treatment, RECIST for complete response (CR), PR, and major response had the same survival prognosis as stable disease (no change), and all patients except those meeting the definition of progressive disease (PD) had to be considered responders to imatinib1 LeCesne et al grouped responders into 6 new tumor response categories, according to their predictions of further disease progression and survival1 The results are consistent with those reported in the phase 2 US/Finland trial, in which OS was the same for patients with an objective response or SD2 The study investigators further concluded that the RECIST criteria are optimal only for identifying resistant GISTs (PD) and are not adequate for the evaluation of imatinib efficacy1 LeCesne A, Van Glabbeke M, Verweij J, et al. Is a stable disease according to RECIST criteria a real stable disease in GIST patients treated with imatinib mesylate (IM) included in the intergroup EORTC/ISG/AGITG trial? [ASCO GI abstract 9510]. J Clin Oncol. 2006;24(suppl):522s. 2. Blanke CD, Demetri GD, Von Mehren M, et al. Long-term follow-up of a phase II randomized trial in advanced gastrointestinal stromal tumor (GIST) patients (pts) treated with imatinib mesylate [ASCO abstract 9528]. J Clin Oncol. 2006;24(suppl):526s. N = 906. TTP, time to tumor progression; CR, complete response; MR, major response; NC, no change; OS, overall survival; y, years. LeCesne A et al. J Clin Oncol. 2006;24(suppl):522s. Abstract 9510.

28 Choi et al: Proposal of Modified CT Response Criteria
Premise: RECIST insensitive in evaluating tumor responses in GIST treated with imatinib Objectives Determine whether changes in tumor size and density on CT correlate with 18FDG-PET responsesa Develop reliable, quantitative CT response criteria Patients: N = 40 (total of 172 lesions) with metastatic GISTs treated with imatinib Methods Patients received pretreatment and 2-month follow-up CT and 18FDG-PET scans Multivariate analysis was carried out using tumor size and density (HU) on CT and SUVmax on 18FDG-PET Patients followed for up to 28 months Choi et al conducted a study to determine whether changes in tumor size and density on CT correlate with FDG-PET responses, with the goal of developing reliable, quantitative CT response criteria RECIST have been shown to be insensitive in evaluating tumor responses in GISTs treated with imatinib1 Choi et al conducted a study to determine whether changes in tumor size and density on CT scans correlate with tumor responses to imatinib by 18FDG-PET and to develop reliable, quantitative CT response criteria1 The study evaluated a total of 172 lesions in 40 patients with metastatic GISTs who received treatment with imatinib1 CT and 18FDG-PET scans were carried out on patients before treatment and 2 months after treatment. Multivariate analysis was carried out with the following parameters: tumor size and density (HU) on CT and maximum standardized uptake value (SUVmax) on 18FDG-PET. Patients were followed for up to 28 months1 Choi H, Charnsangavej C, Faria SC, et al. Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria. J Clin Oncol. 2007;25:1753- 1759. aGood response defined as a 70% decrease in SUVmax to an absolute value of <2.5. HU, Hounsfield unit; SUVmax, maximum standardized uptake value. Choi H et al. J Clin Oncol. 2007;25:

29 Choi et al: Modified CT Response Evaluation Criteria
Definition CR Disappearance of all lesions No new lesions PR A decrease in sizea of ≥10% or a decrease in tumor density (HU) of ≥15% on CT No obvious progression of nonmeasurable disease SD Does not meet the criteria for CR, PR, or PD No symptomatic deterioration attributed to tumor progression PD Increase in tumor size of ≥10% and does not meet criteria of PR by tumor density (HU) on CT New lesions New intratumoral nodules or increase in the size of the existing intratumoral nodules The Choi criteria measure response on the basis of changes in both tumor size and tumor density, whereas RECIST measure response on the basis of changes in tumor size alone The modified CT response evaluation criteria proposed by Choi and colleagues represent a more sensitive alternative to RECIST for monitoring responses to therapy in GIST1 The Choi criteria define PR as a decrease in tumor size of ≥10%, measured as the sum of the longest diameters of target lesions as defined in RECIST, or a decrease in tumor density, measured in HU, of ≥15% on CT1 CR is defined as the disappearance of all lesions and the absence of new lesions1 PD is defined as an increase in tumor size of ≥10% and a failure to meet tumor-density (HU) criteria for PR by CT, the appearance of new lesions, the appearance of new intratumoral nodules, or an increase in size of existing intratumoral nodules1 SD is defined as a failure to meet criteria for CR, PR, or PD, with no symptomatic deterioration attributed to tumor progression1 Choi H, Charnsangavej C, Faria SC, et al. Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria. J Clin Oncol. 2007;25:1753- 1759. aSum of the longest diameters of target lesions as defined in RECIST. Adapted with permission from Choi H et al. J Clin Oncol. 2007;25:

30 Summary: Monitoring GIST and Assessing Response to Treatment
CT and 18FDG-PET are the primary methods of assessing response to imatinib Modified CT response criteria (Choi criteria) are a sensitive and specific method for assessing tumor response to imatinib Based on changes in tumor size and density Outperform conventional size-based criteria (RECIST, SWOG) 18FDG-PET provides an effective tool for rapid assessment of response to imatinib Can be used to clarify equivocal CT results NCCN guidelines/ESMO consensus recommend Regular CT monitoring of patients with GIST after surgery 18FDG-PET as a tool to be used also in surveillance CT and 18FDG-PET are useful in early recognition of the signs of PD CT may be used to detect focal recurrence and clonal resistance 18FDG-PET effective in visualizing reactivated tumor cells when imatinib is withdrawn The primary method of assessing response to imatinib is by anatomic and functional imaging through CT, with or without contrast, and 18FDG-PET NCCN guidelines and ESMO consensus recommendations provide guidance on the use of CT and 18FDG-PET in surveillance of metastatic or recurrent GIST after surgery Conventional criteria (RECIST, SWOG) based on tumor size are limited in assessing responses in the imatinib era and have been shown to significantly underestimated responses in GIST to imatinib treatment Modified CT response criteria (Choi criteria) are a sensitive and specific method for assessing tumor response to imatinib and have been shown to be an excellent predictor of TTP, detecting significant difference between good and poor PET responders CT is useful in early recognition of the signs of progressive GIST after treatment with imatinib and may be used to detect focal recurrence following response GIST progression during imatinib therapy often appears as one or more new, small, intratumoral nodules resistant to imatinib Clonal evolution of resistance may first appear as regions of a responding tumor with increased density The BFR14 trial found that discontinuation of imatinib after initial response usually leads to rapid disease progression Populations of metabolically quiescent tumor cells can rapidly reactivate when imatinib is withdrawn, and reactivation can be visualized by PET imaging

31 Practical Management of Imatinib Therapy for GIST

32 Practical Management of Imatinib Therapy for GIST
Management of AEs is key to compliance with therapy1 Interruption of imatinib therapy often results in rapid tumor progression2 Imatinib differs from IV chemotherapy Oral daily administration Typically taken for long periods of time Long-term adherence to oral cancer therapies problematic3 Adherence with imatinib in CML shown to decline over time4,5 Successful management of AEs associated with imatinib therapy in patients with gastrointestinal stromal tumor (GIST) is a key to compliance with therapy1 Interruption of tyrosine kinase therapy often results in rapid disease progression; therefore, maintaining optimal imatinib dosing is essential to ensuring maintenance of clinical response2 Unlike intravenous (IV) chemotherapy, imatinib is typically administered for long periods of time. Therefore, adherence can be particularly problematic with imatinib Imatinib provides the convenience of oral administration. However, rates of nonadherence to oral cancer therapies have been shown to be high3 Results from studies of adherence with imatinib therapy in patients with chronic myeloid leukemia (CML) suggest adherence declines over time4,5 Van Glabbeke M, Verweij J, Casali PG, et al. Predicting toxicities for patients with advanced gastrointestinal stromal tumours treated with imatinib: a study of the European Organisation for Research and Treatment of Cancer, the Italian Sarcoma Group, and the Australasian Gastro-Intestinal Trials Group (EORTC-ISG-AGITG). Eur J Cancer. 2006;42: Blay JY, Le Cesne A, Ray-Coquard I, et al. Prospective multicentric randomized phase III study of imatinib in patients with advanced gastrointestinal stromal tumors comparing interruption versus continuation of treatment beyond 1 year: the French Sarcoma Group. J Clin Oncol. 2007;25: Partridge AH, Avorn J, Wang PS, Winer EP. Adherence to therapy with oral antineoplastic agents. J Natl Cancer Inst. 2002;94: Tsang J, Rudychev I, Pescatore SL. Prescription compliance and persistency in chronic myelogenous leukemia (CML) and gastrointestinal stromal tumor (GIST) patients on imatinib [ASCO abstract 6119]. J Clin Oncol. 2006;24:330s. Feng W, Henk H, Thomas H, et al. Compliance and persistency with imatinib [ASCO abstract 6038]. J Clin Oncol. 2006;24:310s. CML, chronic myeloid leukemia; IV, intravenous. 1. Van Glabbeke M et al. Eur J Cancer. 2006;42: 2. Blay JY et al. J Clin Oncol. 2007;25: 3. Partridge AH et al. J Natl Cancer Inst. 2002;94: 4. Tsang J et al. J Clin Oncol. 2006;24:330s. Abstract 6119. 5. Feng W et al. J Clin Oncol. 2006;24:310s. Abstract 6038.

33 AE Profile of Imatinib in GIST
Most patients taking imatinib experience AEs during therapy, but the drug is generally well tolerated1,2 AEs usually are mild to moderate Few drug-related discontinuations in GIST trials AEs generally most troublesome in first 2 months of therapy2 Rates of common AEs consistent over 4-year follow-up3 Reports of cardiac adverse events are uncommon1,4 Most imatinib patients experience AEs during therapy, but such events are usually mild to moderate in severity and seldom require discontinuation of therapy1,2 Imatinib therapy in GIST is generally well tolerated, with AEs tending to be most troublesome during the first 2 months of therapy1,2 Long-term (4-year) data indicate that rates of common AEs remain consistent over time3 Cardiotoxicity, including arrhythmia, atrial fibrillation, cardiac arrest, myocardial infarction, angina pectoris, and pericardial effusion, occurs rarely with imatinib treatment.1 Reports of cardiac adverse events are uncommon1,4 Glivec [summary of product characteristics]. Basel, Switzerland: Novartis Pharma AG; 2007. Verweij J, van Oosterom A, Blay JY, et al. Imatinib mesylate (STI-571 Glivec, Gleevec) is an active agent for gastrointestinal stromal tumours, but does not yield responses in other soft-tissue sarcomas that are unselected for a molecular target. Results from an EORTC Soft Tissue and Bone Sarcoma Group phase II study. Eur J Cancer. 2003;39: Blanke C, Joensuu H, Demetri G, et al. Long-term follow up of advanced gastrointestinal stromal tumor (GIST) patients treated with imatinib mesylate. Abstract presented at: 2004 Gastrointestinal Cancers Symposium; January 22-24, 2004; San Francisco, CA. Abstract 2. Perik PJ, Rikhof B, de Jong FA, et al. Results of plasma N-terminal pro B-type natriuretic peptide and cardiac troponin monitoring in GIST patients do not support the existence of imatinib-induced cardiotoxicity. Ann Oncol. 2008; 19: 1. Glivec [summary of product characteristics]. Novartis Pharma AG; 2007. 2. Verweij J et al. Eur J Cancer. 2003;39: 3. Blanke C et al Gastrointestinal Cancers Symposium. Abstract 2. 4. Perik PJ et al. Ann Oncol. 2008:19:

34 Imatinib 800 mg/d: Tolerability and Safety
Phase 3 results demonstrate that doses up to 800 mg/d are generally well tolerated1-3 EORTC 62005: rates of SAEs similar in high- and low-dose groups (38% vs 37%, respectively) Toxicities dose dependent4 Patients who dose-escalate from 400 to 800 mg/d appear to tolerate high dose better2,4 US-Finland S0033: SAEs more common with high vs low dose (63% vs 43%) Results from phase 3 studies demonstrate that doses of imatinib up to 800 mg/d are generally well tolerated1-3 In the US-Finland S0033 trial, rates of serious adverse events (SAEs) were more common with high-dose versus low-dose imatinib. Additionally, dose interruptions and reductions were more common with imatinib 800 mg/d compared with 400 mg/d2 In the European Organisation for Research and Treatment of Cancer (EORTC) trial, rates of SAEs were similar in the 2 dosing groups (38% for imatinib 800 mg/d vs 37% for imatinib 400 mg/d). Dose interruptions and reductions were significantly more common in the high-dose versus low-dose group (P < )3 Analysis of phase 3 results showed that toxicities are dose dependent. However, patients who dose-escalate from 400 to 800 mg/d appear to better tolerate high-dose therapy compared with those patients with a 800-mg/d starting dose2,4 Reichardt P. Optimising therapy for GIST. EJC Suppl. 2006;4(suppl 1):19-26. Blanke CD, Rankin C, Demetri GD, et al. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol. 2008;26: Verweij J, Casali PG, Zalcberg J, et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet. 2004;364: Van Glabbeke M, Verweij J, Casali PG, et al. Predicting toxicities for patients with advanced gastrointestinal stromal tumours treated with imatinib: a study of the European Organisation for Research and Treatment of Cancer, the Italian Sarcoma Group, and the Australasian Gastro-Intestinal Trials Group (EORTC-ISG-AGITG). Eur J Cancer. 2006;42: EORTC, European Organisation for Research and Treatment of Cancer; SAEs, serious adverse events. 1. Reichardt P. EJC Suppl. 2006;4(suppl 1):19-26. 2. Blanke CD et al. J Clin Oncol. 2008;26: 3. Verweij J et al. Lancet. 2004;364: 4. Van Glabbeke M et al. Eur J Cancer. 2006;42:

35 Management of AEs Most AEs associated with imatinib therapy1,2
Mild to moderate (grade 1 or 2) Manageable without dose reduction or discontinuation AEs improve with time on imatinib treatment Management of AEs is vital to maintaining response If toxicity necessitates interruption2,3 Reinitiate therapy without dose reduction Interruption and subtherapeutic dosing may increase risk of progression and resistance Successful management of AEs without interruption of therapy or reduction of dose is vital to maintaining response1-3 Similar to other cytotoxic treatments for cancer, imatinib therapy is associated with side effects1 However, most AEs associated with imatinib therapy are mild to moderate (grade 1 or 2) and manageable without reduction in dosage or discontinuation of treatment1 Often, common AEs, such as fluid retention, diarrhea, nausea, fatigue and rash, may improve with continued therapy2 Management of AEs is important in GIST and other cancers; interruption of therapy or dose reduction may lead to loss of response3 If toxicities fail to resolve over time, therapy may be interrupted. Reinitiation of therapy without reduction of dose is recommended1 Extended therapy interruption and subtherapeutic dosing carry the risk of progression and resistance2,3 Guilhot F. Indications for imatinib mesylate therapy and clinical management. Oncologist. 2004;9: Demetri G, Benjamin R, Blanke CD, et al. NCCN Task Force report: optimal management of patients with gastrointestinal stromal tumor (GIST)—expansion and update of NCCN Clinical Practice Guidelines. J Natl Compr Canc Netw. 2004;2(suppl 1):S1-S26. Blay JY, Berthaud P, Perol D, et al. Continuous vs intermittent imatinib treatment in advanced GIST after one year: a prospective randomized phase III trial of the French Sarcoma Group [ASCO abstract 9006]. Proc Am Soc Clin Oncol. 2004;23(suppl):815. 1. Guilhot F. Oncologist. 2004;9: 2. Demetri GD et al. J Natl Compr Canc Netw. 2004;2(suppl 1):S1-S26. 3. Blay JY et al. Proc Am Soc Clin Oncol. 2004;23:815. Abstract 9006.

36 Managing Progressive Disease

37 Discontinuation of Imatinib Increases Risk of GIST Progression
Patients who achieved clinical benefit after 12 months were randomized to continue or interrupt imatinib therapy Interrupt-therapy arm was discontinued due to high rates of disease progression Reintroduction of imatinib restored tumor control in all but 1 progressing patient who refused to restart imatinib therapy A study comparing continuation versus discontinuation of imatinib treatment in advanced GIST after 12 months of successful therapy found that discontinuation significantly increased the risk of GIST progression. Reinstitution of imatinib treatment restored responses in most, but not all, patients in the BFR14 trial1 Between May 2003 and April 2004, the BFR14 trial, conducted by the French Sarcoma Group, randomized 58 responding patients (complete response [CR], partial response [PR], and stable disease [SD]) to imatinib-continuation and imatinib-interruption arms after 1 year of treatment, with PFS as the end point1 In March 2004, randomization was halted prematurely by the data-monitoring committee when an excessive number of progressions occurred in the interrupted-treatment arm1 As of June 2008, median PFS was 29 months in the imatinib-continued arm after 1 year of treatment compared with 7 months in the imatinib-interruptions arm (P < )2 Patients in the interrupted-treatment arm of the trial had a comparable time to secondary resistance to imatinib after its reintroduction to those of patients who continued imatinib treatment (P = 0.590)2 With longer imatinib therapy (3 years), the 1-year PFS was 92% in the continued-treatment arm versus 30% in the interrupted-treatment arm (P < )2 Among the 20 patients who had progressed, when imatinib treatment was resumed after interruption, disease control was achieved in 19 patients (95%), and treatment interruption after 3 years did not affect 1-year OS between arms3 Blay JY, Le Cesne A, Ray-Coquard I, et al. Prospective multicentric randomized phase III study of imatinib in patients with advanced gastrointestinal stromal tumors comparing interruption versus continuation of treatment beyond 1 year: the French Sarcoma Group. J Clin Oncol. 2007;25: Pérol D, Dômont J, Ray-Coquard IL, et al. Does interruption of imatinib (IM) in responding GIST patients after one year of treatment influence the secondary resistance to IM after its reintroduction? Updated results of the prospective French Sarcoma Group randomized phase III trial on long term survival [ASCO abstract 10556]. J Clin Oncol. 2008;26:567s. Adenis A, Cassier PA, Bui BN, et al. BFR14 trial: does interruption of imatinib (IM) in responding patients after three years of treatment influence outcome of patients with advanced GIST included in the BFR14 trial? [ASCO abstract 10522]. J Clin Oncol. 2008;26:558s. CI, confidence interval; CONT, continuous; GIST, gastrointestinal stromal tumor; INT, interrupted; PD, progressive disease; PFS, progression-free survival. Adapted with permission from Adenis A et al. J Clin Oncol. 2008;26:558s.

38 Causes of GIST Progression
Causes of tumor progression Therapy interruption or discontinuation Lack of compliance Patient-specific pharmacokinetic factors causing subtherapeutic drug levels Mutations Pharmacokinetic factors Low imatinib plasma trough levels correlate with poor clinical outcome Resistance is a common cause of disease progression in patients with GIST who receive imatinib therapy; however, it is often manageable Common causes of tumor progression in GIST patients receiving imatinib therapy include interruption or discontinuation of therapy, lack of compliance, patient-specific pharmacokinetic factors that cause subtherapeutic drug levels, and mutations1 Resistance is probably the most common cause of progression in imatinib-treated GIST1 A recent analysis from B2222 study showed that patients with a low imatinib trough plasma exposure (<1100 ng/mL) had lower rates of clinical benefit and faster time to progression2 von Mehren M, Watson JC. Gastrointestinal stromal tumors. Hematol Oncol Clin North Am. 2005;19: von Mehren M, Wang Y, Joensuu H, et al. Imatinib pharmacokinetics (PK) and its correlation with clinical response in patients with unresectable/metastatic gastrointestinal stromal tumor (GIST) [ASCO abstract 4523]. J Clin Oncol. 2008;26:218s. von Mehren M et al. Hematol Oncol Clin North Am. 2005;19:

39 Imatinib Plasma Levels Correlate With Clinical Benefit in Patients With GIST
Imatinib PK and its correlation with clinical response in GIST patients are not well understood Analyses of PK correlations with clinical outcomes and benefits were performed retrospectively from study B2222 Patients were grouped into quartiles (Q) according to imatinib TPC: Q1: Cmin <1110 ng/mL Q2 + Q3: Cmin ≥1110 to <2040 ng/mL Q4: Cmin ≥2040 ng/mL GIST patients with a low imatinib trough plasma exposure (<1100 ng/mL) showed lower rates of clinical benefit and faster time to progression A pharmacokinetic study of a subset of patients from the randomized phase 2 B2222 study, to investigate the relationship between imatinib levels and clinical outcome, demonstrated a positive correlation between imatinib trough plasma concentrations (TPC) and clinical benefit Demetri et al analyzed a subset of patients (n = 73) from the B2222 trial to determine whether imatinib TPC correlated with overall responses to treatment. Patients were grouped into quartiles (Q) according to imatinib TPC: Q1: Cmin <1110 ng/mL Q2 + Q3: Cmin ≥1110 to <2040 ng/mL Q4: Cmin ≥2040 ng/mL Clinical benefit was achieved by 67% of Q1 patients versus 81% and 84% of Q2-Q3 and Q4 patients, respectively Patients with a low imatinib trough plasma exposure (<1100 ng/mL) progressed faster (median 11.3 months) than patients with a high imatinib trough plasma exposure (>1100 ng/mL) (30.6 months; P = ) Demetri GD, Wang Y, Wehrle E, et al. Correlation of imatinib plasma levels with clinical benefit in patients (pts) with unresectable/metastatic gastrointestinal stromal tumors (GIST). Presented at: 2008 ASCO Gastrointestinal Cancers Symposium; January 25-27, 2008; Orlando, FL. Abstract 3. PK, pharmacokinetics; TPC, trough plasma concentration. Demetri GD et. al Presented at: 2008 ASCO Gastrointestinal Cancers Symposium; Abstract 3.

40 Overall Objective Clinical Benefit by Imatinib TPC Quartiles
Pivotal Phase 2 Trial: Higher Imatinib Trough Plasma Level Correlates With Clinical Benefit Imatinib TPC Quartiles Q1 (n = 18) Q2-Q3 Combined Q4 (n = 19) Q2 (n = 18) Q3 (n = 18) Mean, ng/mL 797 ± 227 1250 ± 87 1640 ± 170 2550 ± 530 CV, % 28.4 6.9 10.5 20.9 Range Overall Objective Clinical Benefit by Imatinib TPC Quartiles A pharmacokinetic study of a subset of patients from the B2222 pivotal phase 2 trial demonstrated a positive correlation between imatinib TPC and clinical benefit (CR + PR + SD) Demetri et al analyzed a subset of patients (n = 73) from the B2222 trial to determine whether imatinib TPC correlated with overall responses to treatment. Patients were grouped into quartiles (Q) according to imatinib TPC Q1: Cmin <1110 ng/mL Q2 + Q3: Cmin ≥1110 to <2040 ng/mL Q4: Cmin ≥2040 ng/mL The overall mean was 1570 ng/mL ranging from 410 to 4180 ng/mL Clinical benefit was achieved by 67% of Q1 patients versus 81% and 84% of Q2-Q3 and Q4 patients, respectively Patients in Q1 showed a lower rate of benefit than patients in the upper quartiles (P = by Chi-square test) von Mehren M, Wang Y, Joensuu H, et al. Imatinib pharmacokinetics (PK) and its correlation with clinical response in patients with unresectable/metastatic gastrointestinal stromal tumor (GIST) [ASCO abstract 4523]. J Clin Oncol. 2008;26:218s. Response n (%) Q1 (n = 18) Q2-Q3 (n = 36) Q4 (n = 19) CR + PR + SD 12 (67) 29 (81) 16 (84) PD/unknown 6 (33) 7 (19) 3 (16) Q, quartile; CV, coefficient of variation; CR, complete response; PR, partial response; SD, stable disease. von Mehren M et al. Presented at: 44th ASCO Annual Meeting; Abstract 4523.

41 Time to Progression in Patients With Imatinib PK by Cmin Quartiles
Imatinib trough plasma level correlated with time to progression Patients with a low imatinib trough plasma exposure (<1100 ng/mL) progressed faster (median 11.3 months) than patients with a high imatinib trough plasma exposure (>1100 ng/mL) (30.6 months; P = ) Demetri GD, Wang Y, Wehrle E, et al. Correlation of imatinib plasma levels with clinical benefit in patients (pts) with unresectable/metastatic gastrointestinal stromal tumors (GIST)[ASCO GI abstract 3]. Presented at: 2008 ASCO Gastrointestinal Cancers Symposium; January 25-27, 2008; Orlando, FL. Cmin, minimum concentration. Adapted with permission from Demetri GD et al. Presented at: ASCO Gastrointestinal Cancers Symposium; Abstract 3.

42 Primary and Secondary Resistance: Definition
Primary Resistance1,2 (no response) Secondary (Acquired) Resistance1,2 (loss of response) No response to therapy Early progression Within first 6 months Affects small percentage of patients Initial response to or stabilization on imatinib Develop progressive disease After 6 months Imatinib resistance is defined as primary or secondary (acquired) depending on the length of initial response to treatment with imatinib1 Primary resistance is defined as no response to therapy. With primary resistance, progression occurs shortly after initiation of therapy (within 6 months)1,2 This type of resistance affects a small percentage of patients who receive imatinib1 Secondary or acquired resistance is defined as disease progression following initial stabilization on or response to imatinib therapy1 With secondary resistance, disease progression occurs after 6 months of therapy1,2 von Mehren M, Watson JC. Gastrointestinal stromal tumors. Hematol Oncol Clin North Am. 2005;19: Blay JY, Bonvalot S, Casali P, et al. Consensus meeting for the management of gastrointestinal stromal tumors. Report of the GIST Consensus Conference of March 2004, under the auspices of ESMO. Ann Oncol. 2005;16: 1. von Mehren M et al. Hematol Oncol Clin North Am. 2005;19: 2. Blay JY et al. Ann Oncol. 2005;16:

43 Mechanisms of Mutational Resistance to Imatinib (cont’d)
Overexpression or amplification of KIT or PDGFRA gene1-3 Activation of downstream signal pathways bypassing KIT1-3 P-glycoprotein overexpression1 Antiapoptosis1 Decrease in imatinib intracellularly due to increased metabolism (eg, p450, -1 acid glycoprotein)1 Mutational resistance may result from KIT or PDGFRA gene amplification or the activation of alternative kinases1,2 Other potential mechanisms of resistance include overexpression or amplification of the KIT or PDGFRA gene and activation of downstream signal pathways bypassing KIT1-3 Additionally, P-glycoprotein overexpression, antiapoptosis, and a decrease in imatinib intracellularly due to increased metabolism (eg, p450, -1 acid glycoprotein) may be implicated in the development of resistance to imatinib1 Chen LL, Sabripour M, Andtbacka RH, et al. Imatinib resistance in gastrointestinal stromal tumors. Curr Oncol Rep. 2005;7: Fletcher JA, Corless CL, Dimitrijeviz S, et al. Mechanisms of resistance to imatinib mesylate (IM) in advanced gastrointestinal stromal tumor (GIST) [ASCO abstract 3275]. Proc Am Soc Clin Oncol. 2003;22:815. Heinrich MC, Corless CL, Blanke CD, et al. Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. J Clin Oncol. 2006;24: 1. Chen LL et al. Curr Oncol Rep. 2005;7: 2. Heinrich MC et al. J Clin Oncol. 2006;24: 3. Fletcher JA et al. Proc Am Soc Clin Oncol. 2003;22:815. Abstract 3275.

44 Phase 3 Studies: Response Rates After Crossover to Imatinib 800 mg/d
One-third of patients benefited from dose increase at progression 62005 Trial1 S0033 Trial2 In the and S0033 phase 3 studies, approximately one-third of patients who crossed over benefited from dose increase at progression1,2 Imatinib has been approved worldwide for the treatment of GIST at a dose of 400 mg/d3,4 The EORTC study and Southwestern Oncology Group (SWOG) S0033 analysis compared response to imatinib 400 mg/d or 800mg/d1,2 Among 241 patients in trial who were available for follow-up, 133 (55%) patients crossed over from the 400-mg/d imatinib starting dose to 800-mg/d dosing. The clinical benefit rate following crossover was 29%, comprising 2% partial responses and 27% stable disease. The median progression-free survival (PFS) following crossover was 81 days. One year after crossover, 18.1% of patients were still alive and progression free1 Similarly, in the S0033 study, among 746 patients who were available for follow-up, 117 (16%) patients were assessable for response following crossover. The clinical benefit rate following crossover was composed of 12 patients (3%) with complete response, 148 patients (42%) with partial response, and 76 patients (22%) with stable disease. Following crossover, 99 died or progressed with a median PFS of 5 months, and 76 died with a median OS of 19 months2 Both studies demonstrated that increasing the imatinib dose from 400 mg/d to 800 mg/d at the time of progression with the lower dose was safe and provided a clinical benefit in about one-third of patients1,2 Zalcberg JR, Verweij J, Casali PG, et al. Outcome of patients with advanced gastro-intestinal stromal tumours crossing over to a daily imatinib dose of 800 mg after progression on 400 mg. Eur J Cancer. 2005;41: Blanke CD, Rankin C, Demetri GD et al. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the Kit receptor tyrosine kinase: S0033. J Clin Oncol 2008:26: Blay JY, Bonvalot S, Casali P, et al. Consensus meeting for the management of gastrointestinal stromal tumors. Report of the GIST Consensus Conference of March 2004, under the auspices of ESMO. Ann Oncol. 2005;16: Demetri GD, Benjamin RS, Blanke CD, et al. NCCN Task Force report: management of patients with gastrointestinal stromal tumor (GIST)—update of the NCCN Clinical Practice Guidelines. J Natl Compr Can Netw. 2007;5 (suppl 2):S1-S29. AI, assessment inadequate. 1. Zalcberg JR et al. Eur J Cancer. 2005;41: 2. Blanke CD et al. J Clin Oncol. 2008:26:

45 Imatinib Dose Optimizing in GIST
Phase 3 studies have demonstrated the feasibility of dose escalation in PD1,2 Approximately one-third of patients with PD achieve clinical benefit (objective response or stable disease) after dose increase1,2 Available safety data suggest that dose escalation to 800 mg/d has no adverse effect on safety and tolerability3 Results from phase 2 and 3 studies suggest that escalation to 800 mg/d imatinib is feasible and safe in GIST patients whose disease progresses at lower doses1 Clinical studies have demonstrated the feasibility of imatinib dose escalation in the presence of PD1-3 In these studies, 103 patients were escalated to a daily dose of imatinib 800 mg. Results showed a PR in 6 patients and disease stabilization in 21 patients, resulting in an overall clinical benefit of 26%1 Available safety data suggest that in patients with PD already receiving imatinib 400 or 600 mg/d, increasing the imatinib dose to 800 mg/d does not seem to affect the safety profile of the agent1 Results from the crossover arm of the phase 3 EORTC study suggest that, although there was a significant increase in anemia and fatigue with the higher dose, the severity of other adverse events was similar despite a doubling of the imatinib dose2 Similarly, results from the North American Intergroup S0033 study suggest that crossover to high-dose imatinib is feasible with a low incidence of required dose modifications3 Glivec [summary of product characteristics]. Basel, Switzerland: Novartis Pharma AG; 2007. Zalcberg JR, Verweij J, Casali PG, et al. Outcome of patients with advanced gastro-intestinal stromal tumours crossing over to a daily imatinib dose of 800 mg after progression on 400 mg. Eur J Cancer. 2005;41: Blanke CD, Rankin C, Demetri GD, et al. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the Kit receptor tyrosine kinase: S0033. J Clin Oncol. 2008;26: 1. Zalcberg JR et al. Eur J Cancer. 2005;41: 2. Blanke CD et al. J Clin Oncol. 2008;26: Glivec [summary of product characteristics]. Novartis Pharma AG; 2007.

46 Use of Surgery and Imatinib Therapy in Recurrent Disease
Recurrent GIST should be managed as metastatic disease and treated with imatinib1-3 Imatinib therapy may be complemented by surgical resection Provides survival benefit with continued use of imatinib4 May provide a survival benefit even in imatinib-resistant patients5 Recommended for isolated clonal progression1 Recurrent GIST should be managed as metastatic disease and treated with imatinib1,2 According to NCCN guidelines and ESMO consensus conference recommendations, recurrent GIST should be managed as metastatic disease and treated with imatinib1,2 Use of imatinib with or without surgery in patients with recurrent or metastatic disease is recommended until oral intake is no longer feasible. Surgical resection is indicated in instances of isolated clonal progression. Studies in which imatinib has been discontinued without use of an alternate treatment showed increases in tumor activity1,3 Demetri GD, Benjamin RS, Blanke CD, et al. NCCN Task Force report: management of patients with gastrointestinal stromal tumor (GIST)—update of the NCCN Clinical Practice Guidelines. J Natl Compr Can Netw. 2007;5 (suppl 2):S1-S29. Blay JY, Bonvalot S, Casali P, et al. Consensus meeting for the management of gastrointestinal stromal tumors. Report of the GIST Consensus Conference of March 2004, under the auspices of ESMO. Ann Oncol. 2005;16: von Mehren M, Watson JC. Gastrointestinal stromal tumors. Hematol Oncol Clin North Am. 2005;19: Conclusion: Continuation of imatinib is mandatory in recurrent and metastatic GIST. Imatinib may be used as an investigational adjuvant and neoadjuvant agent to surgery in primary disease1-5 1. Demetri GD et al. J Natl Compr Canc Netw. 2007;5(suppl 2):S1-S29. 2. Blay JY et al. Ann Oncol. 2005;16: 3. Casali PG et al. Ann Oncol. 2008;19(suppl 2):ii35-ii38. 4. Hohenberger P et al. J Clin Oncol. 2006;24(suppl):520s. Abstract 9500. 5. Nishida T et al. J Clin Oncol. 2006;24(suppl):531s. Abstract 9548.

47 Progressive GIST: When to Consider a Second-Line Agent
Steps to take to clarify cause of resistance1 Verify imatinib compliance and check blood level Identify possible pharmacokinetic factors Continue imatinib therapy: effective KIT/PDGFRA suppression must be maintained1 Use of second-line inhibitor therapy1 Imatinib dose optimization Surgical debulking of progressive lesions (where feasible) Consider use of KIT-PDGFR inhibitors After imatinib dose optimization Local therapy may be considered Sunitinib is currently the second option after imatinib dose optimization or in patients intolerant to imatinib Consider using promising new inhibitors (nilotinib, dasatinib) currently under investigation Use of alternate inhibitor therapy in combination with imatinib may be needed after clarifying the possible causes of resistance, considering the feasibility of re-resection, and optimizing imatinib dosing Several factors may contribute to imatinib resistance in GIST. Therefore, it is important to clarify, where possible, the cause of resistant, progressive disease1 It is important to verify imatinib compliance and to identify possible pharmacokinetic factors that may compromise the efficacy of imatinib1 Imatinib dose optimization often results in stabilization of disease in patients started on imatinib 400 mg/d. Dose optimization may result in tumor stabilization in as many as 35% of patients. Surgical debulking of progressive lesions and radioablation should be considered when feasible1 Imatinib therapy should be continued to maintain effective KIT and PDGFRA suppression. Use of an alternate inhibitor in combination with imatinib is indicated in PD when other measures are exhausted1 Resistance or progression calls for a reevaluation of therapy, not an immediate switch to a different agent2 von Mehren M, Watson JC. Gastrointestinal stromal tumors. Hematol Oncol Clin North Am. 2005;19: Blanke CD, Rankin C, Demetri GD, et al. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the Kit receptor tyrosine kinase: S0033. J Clin Oncol. 2008;26: 1. von Mehren M et al. Hematol Oncol Clin North Am. 2005;19: 2. Blanke CD et al. J Clin Oncol. 2008;26:

48 Imatinib Treatment for Adjuvant GIST

49 97 discontinued treatment early 87 discontinued treatment early
ACOSOG Z9001: Trial Schema 97 discontinued treatment early 30 events 5 GIST-unrelated deaths Imatinib (359 randomized) (337 treated) 713 patients randomized IM 400 mg/day or placebo for 1 yr (Phase III) 778 patients 87 discontinued treatment early 70 events 5 GIST-related deaths 3 GIST-unrelated deaths Placebo (354 randomized) (345 treated) Phase III, randomized, double-blind, placebo-controlled multi-center trial Eligibility: Patients >18 years with localized and primary GIST; KIT-positive tumors (>3 cm ); complete surgical resection Endpoints: Primary: RFS; secondary: OS and safety Dose modifications upon grade 3 or 4 events PD patients unblinded: If placebo  IM 400 mg/d; or If IM 400 mg/d  IM 800 mg/d

50 Patient characteristics
Parameters Placebo (n=354) Imatinib (n=359) Age, median (range) 58 (18-91) 59 (18-88) Gender, n (%) Female 163 (46.0%) 189 (52.6%) Male 191 (54.0%) 170 (47.4%) Performance Status, n (%) 265 (74.9%) 281 (78.3%) 1 81 (22.9%) 74 (20.6%) 2 8 (2.3%) 4 (1.1%) Days between resection & randomization; median (range) 59 (15-96) 57 (20-74) Patients in both arms had similar clinicopathologic features The intent-to-treat population included 713 patients, of whom 354 (49.6%) were assigned to placebo and 359 (50.4%) to imatinib Patients were randomized to study treatment at a median of 8.3 weeks after surgical resection Overall, 65 patients did not meet all eligibility requirements for the study (33 patients in the placebo arm and 32 patient in the imatinib arm) DeMatteo RP, Ballman KV, Antonescu CR, et al. Randomized trial of adjuvant imatinib mesylate following the resection of localized, primary gastrointestinal stromal tumor (GIST). Lancet. 2009; in press.

51 Patient characteristics (continued)
Parameters Placebo (n=354) Imatinib (n=359) Tumor size, n (%) >3 and <6 cm 149 (42.1%) 143 (39.8%) >6 and <10 cm 119 (33.6%) 123 (34.3%) >10 cm 86 (24.3%) 93 (25.9%) Margins, n (%) R0 330 (93.2%) 325 (90.5%) R1 23 (6.5%) 34 (9.5%) Unknown 1 (0.3%) 0 (0.0%) Tumor origin, n (%) Stomach 235 (66.4%) 209 (58.2%) Small intestine 102 (28.8%) 125 (34.8%) Rectum 5 (1.4%) Other 12 (3.4%) 18 (5.0%) 2 (0.6%) The imatinib and placebo arms of Z9001 had similar clinicopathologic features The two arms were well-balanced with respect to tumor size, tumor site, and surgical margins The vast majority of patients in Z9001 had undergone R0 resection DeMatteo RP, Ballman KV, Antonescu CR, et al. Randomized trial of adjuvant imatinib mesylate following the resection of localized, primary gastrointestinal stromal tumor (GIST). Lancet. 2009; in press. R0 – negative microscopic margins; R1 – positive microscopic margins

52 Recurrence-free Survival (RFS)*
Median follow-up: 19.7 months Estimated 1-year RFS (95% CI): Imatinib: 98% (96-100) Placebo: 83% (78-88) HR = 0.35 ( ) P < CI, confidence interval; HR, hazard ratio Adjuvant imatinib improved 1-year RFS compared with placebo following surgical resection of primary GIST 3 cm in size After a median follow-up of 19.7 months, the estimated 1-year RFS was 98% (95% confidence interval [CI]: ) in the imatinib arm compared with 83% in the placebo arm. The overall hazard ratio was 0.35 (95% CI: ; P < ) These findings indicate that imatinib reduced the hazard of tumor recurrence by 65% compared with placebo The rate of recurrence on the imatinib arm appeared to increase after approximately 18 months (ie, 6 months after completion of study treatment). This raises the possibility that treatment with adjuvant imatinib for longer periods may further extend RFS DeMatteo RP, Ballman KV, Antonescu CR, et al. Randomized trial of adjuvant imatinib mesylate following the resection of localized, primary gastrointestinal stromal tumor (GIST). Lancet. 2009; in press. Events experienced: Imatinib: 8.0% (30) Placebo: 20.0% (70) *All randomized patients were included in the analysis; recurrence-free survival was defined as the time from patient registration to the development of tumor recurrence or death from any cause. Intention-to-treat analyses were done for recurrence-free survival (ie, analyzed patients by randomized group). 52

53 Recurrence-free Survival (Tumor size)
size >3 and <6 cm size >6cm and <10cm Imatinib adjuvant therapy results in significantly longer RFS in each of the tumor size categories compared to placebo Patients with tumor size >10 cm have the longest survival on imatinib therapy at 2 years size >10cm 53

54 Overall Survival (OS)*
No difference in OS between imatinib and placebo adjuvant therapies Longer follow-up might reveal a longer OS *All randomized patients were included in the analysis; Overall survival was defined as the time from patient registration to death from any cause. Intention-to-treat analyses were done for overall survival (ie, analyzed patients by randomized group). 54

55 Reduction / interruption of treatment
713 patients randomized Imatinib (n=359) 337 received treatment 22 did not receive treatment 32 ineligible patients Placebo (n=354) 345 received treatment 9 did not receive treatment 33 ineligible patients 97 (27.0%) discontinued treatment early 57 (15.9%) for adverse events 1 (<1%) for disease recurrence 15 (4.2%) for patient withdrawal 24 (6.7%) for other/missing reasons 87 (24.6%) discontinued treatment early 11 (3.1%) for adverse events 41 (11.6%) for disease recurrence 20 (5.6%) for patient withdrawal 15 (4.2%) for other/missing reasons Most patients in both arms of Z9001 completed the 1-year of study treatment. Thirty-one patients did not receive study treatment (9 patients in the placebo arm and 22 patients in the imatinib arm) Overall, 184 patients (25.8%) stopped study treatment prematurely. Discontinuation was more likely to be due to adverse events in the imatinib arm, whereas it was more likely to be due to tumor recurrence in the placebo arm (P < ) Dose reductions and/or interruption was more common in the imatinib arm than in the placebo arm (16.4% vs 4.8%) and mostly was caused by adverse events (14.5% vs 2.8%) DeMatteo RP, Ballman KV, Antonescu CR, et al. Randomized trial of adjuvant imatinib mesylate following the resection of localized, primary gastrointestinal stromal tumor (GIST). Lancet. 2009; in press. Grade 3 or 4 AEs: 31.0% (n=104) Grade 3 or 4 AEs: 18.0% (n=63) 184 (26%) patients discontinued therapy; the main reasons included : Adverse events (AEs): imatinib (n=57) vs. placebo (n=11) (P < ) Tumor recurrence: imatinib (n=1) vs. placebo (n=41) (P < )

56 Safety / Tolerability Adverse Event Placebo (n=345) Imatinib (n=337)
Grade 3 Grade 4 Neutropenia 3 (<1%) 1 (<1%) 7 (2%) 5 (1%) Fatigue 4 (1%) 2 (<1%) Dermatitis 11 (3%) Abdominal pain 6 (1%) 12 (3%) Nausea 8 (2%) Vomiting Diarrhea 10 (2%) ALT AST Edema Hyperglycemia Hypokalemia Syncope Dyspnea Adjuvant imatinib was generally well tolerated. Grade 1 or 2 adverse events were common and mostly involved GI effects (mild diarrhea, nausea, and flatulence), headache, rash, periorbital or peripheral edema, fatigue, or myalgias/arthralgias Overall, 647 of the 682 patients (94.9%) who received at least 1 dose of imatinib or placebo experienced at least 1 adverse event Grade 3 or 4 events occurred at a higher rate in the imatinib arm than in the placebo arm. Sixty-three patients (18.3%) in the placebo arm and 104 patients (30.9%) in the imatinib arm had grade 3 or 4 adverse events DeMatteo RP, Ballman KV, Antonescu CR, et al. Randomized trial of adjuvant imatinib mesylate following the resection of localized, primary gastrointestinal stromal tumor (GIST). Lancet. 2009; in press. ALT, alanine aminotransferase; AST, aspartate aminotransferase

57 Summary Imatinib at 400 mg/d is safe and well tolerated when administered as adjuvant therapy after complete resection of primary GIST Adjuvant imatinib resulted in a significant improvement in RFS in patients with all tumor sizes Especially relevant for high-risk patients (e.g. tumor size ≥10 cm or high mitotic rate) since this patient population has a 50% higher chance of recurrence at 2 years without adjuvant therapy OS between imatinib and placebo groups comparable at this time A longer follow-up period is likely required to observe differences Ongoing trials in the adjuvant setting are under way to determine appropriate treatment duration of imatinib and impact on OS SSGXVIII/AIO EORTC 62024 In the phase 3 ACOSOG Z9001 trial, adjuvant imatinib resulted in a significant improvement in RFS, with increased benefit evident in patients with larger tumor volumes Imatinib 400 mg/d is safe and well tolerated when administered as adjuvant therapy after primary resection Adjuvant imatinib improves RFS, with increased benefit evident in patients with larger tumor volumes OS has not been altered at this time; however, the follow-up period is short Currently, there are 2 ongoing randomized trials to identify how imatinib affects OS in an adjuvant setting EORTC 62024 SSGXVIII/AIO DeMatteo RP, Ballman KV, Antonescu CR, et al. Randomized trial of adjuvant imatinib mesylate following the resection of localized, primary gastrointestinal stromal tumor (GIST). Lancet. 2009; in press.


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