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GIST Overview

GIST Overview. 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. GI, gastrointestinal; HU, Hounsfield units.

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GIST Overview

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  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 GI, gastrointestinal; HU, Hounsfield units. Images adapted with permission from Choi H et al. Am J Roentgenol. 2004;183:1619-1628. Miettinen M et al. Arch Pathol Lab Med. 2006;130:1466-1478.

  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 1. Miettinen M et al. Virchows Arch. 2001;438:1-12. 2. Fletcher CDM et al. Hum Pathol. 2002;33:459-465. 3. Goettsch WG et al. Eur J Cancer. 2005;41:2868-2872. 4. Nilsson B et al. Cancer. 2005;103:821-829. 5. Tryggvason G et al. Int J Cancer. 2005;117:289-293. 6. Rubio J et al. Eur J Cancer. 2007;43:144-148. 7. Mucciarini C et al. BMC Cancer. 2007;7:230.

  4. GIST: Clinical Presentation Symptoms of GIST at Diagnosis1 • 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 1. Miettinen M et al. Hum Pathol. 1999;30:1213-1220. 2. Ghanem N et al. Eur Radiol.2003;13:1669-1678.

  5. Autopsy 10% Incidental 21% 69% Symptomatic Circumstances of GIST Detection Approximately one-third of GISTs are asymptomatic1,2 • Kindblom LG. http://www.asco.org/portal/site/ASCO/menuitem.d3934b88626d03a781d54d10ee37a01d/?vgnextoid=8a7ca1f903878010VgnVCM100000f2730ad1RCRD&spk=Kindblom%2C+Lars-Gunnar+%5Bfau%5D. • Miettinen M et al. Hum Pathol. 1999;30:1213-1220.

  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 60% Small intestine 25% 1. Corless CL et al. Annu Rev Pathol. 2008;3:557-586.

  7. 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 KIT and PDGFRa Receptor Structures • SCF or PDGF binding site • 5 IgG domains Cell membrane 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;14:517-535. 2. Corless CLet al. Annu Rev Pathol. 2008;3:557-586.

  8. Substrate Effector Kinase domains ADP P P P P P P P P SIGNALING Normal KIT Signaling A substrate protein (eg, PI3 kinase) is phosphorylated by KIT kinase1,2 Activation of the substrate initiates a signaling cascade, culminating in cellproliferation and survival1,2 ATP ADP, adenosine diphosphate. 1. Savage DG et al. N Engl J Med. 2002;346:683-693. 2. Scheijen B et al. Oncogene. 2002;21:3314-3333.

  9. Normal Biologic Function of KIT Receptor Tyrosine Kinase 1. Taylor ML et al. Hematol OncolClin North Am. 2000;14:517-535. 2. Beghini A et al. Cancer. 2001;92:657-662.

  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 1. Corless CL et al. Annu Rev Pathol. 2008;3:557-586. 2. Heinrich CM et al. J Clin Oncol. In press. 3. Hirota S et al. Science. 1998;279:577-580. 4. Sommer G et al. Proc Natl Acad Sci U S A. 2003;100:6706-6711. 5. Agaimy A et al. Am J Surg Pathol. 2007;31:113-120. 6. Kawanowa K et al. Hum Pathol. 2006;37:1527-1535. 7. Abraham SC et al. Am J Surg Pathol. 2007;31:1629-1635.

  11. Histopathology • 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%) Spindle cell Epithelioid cell Mixed morphology1 • Fletcher CD et al. Hum Pathol. 2002;33:459-456. • Corless CL et al. Annu Rev Pathol. 2008;3:557-586.

  12. Imatinib Treatment for Unresectable or Metastatic GIST

  13. Algorithm: Imatinib Treatment in Unresectable or Metastatic GIST1,2 MetastaticKIT exon 9+ Imatinib 800 mg/d Unresectable Imatinib 400 mg/d Metastatic Imatinib 400 mg/d Progression OR or SD OR or SD Continue imatinib Secondary surgery Continue imatinib Dose-escalate Imatinib 800 mg/d Progression OR or SD Continue imatinib Limited/Local Generalized/ Systemic 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.2.2008. www.nccn.org. 3. Demetri GD et al. J Natl Compr Canc Netw. 2007;5(suppl 2):S1-S29.

  14. Imatinib in GIST: Rationale 1. Manley PW et al. Eur J Cancer. 2002;38(suppl 5):S19-S27. 2. Heinrich MC et al. Hum Pathol. 2002;33:484-495.

  15. Kinase domains ATP P P P P Imatinib mesylate SIGNALING 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 1. Savage DG et al. N Engl J Med. 2002;346:683-693. 2. Scheijen B et al. Oncogene. 2002;21:3314-3333.

  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 Imatinib (600 mg/d) CT, computed tomography; MRI, magnetic resonance imaging. Demetri GD et al. N Engl J Med. 2002;347:472-480.

  17. Pivotal Phase 2 Trial: Best Observed Rates of Response to Imatinib Tumor Control Based on Slide 53 from IM TX deck 600 mg/d (n = 74) 400 mg/d (n = 73) SD CR PR PR SD CR 63 Months’ Median Follow-up2 CR, complete response. Blanke CD et al. J Clin Oncol. 2008;26:620-625.

  18. Pivotal Phase 2 Trial: Kaplan-Meier Estimate of OS Since Start of Study by Best Response B2222 Study (63 Months’ Median Follow-up) CI, confidence interval; LL, lower limit; N/A, not available; UL, upper limit. Adapted with permission ofBlanke CD et al. J Clin Oncol. 2008;26:620-625.

  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 SWOG, Southwest Oncology Group; TTP, time to progression. 1. Demetri GD et al. N Engl J Med. 2002;347:472-480. 2. Blanke CD et al. J Clin Oncol. 2008;26:620-625. 3. Blanke C et al. ASCO Gastrointestinal Cancers Symposium; 2007. Abstract 21. 4. Demetri GD et al. ASCO Gastrointestinal Cancers Symposium; 2008. Abstract 3.

  20. Phase 3 Trials: Design EORTC/ISG/AGITG Study 620051 North American Intergroup Study S00332 Imatinib (400 mg/d) FollowforPFS Metastatic or unresectable GIST PD Imatinib (800 mg/d) 1. Verweij J et al. Lancet. 2004;364:1127-1134. 2. Blanke CD et al. J Clin Oncol. 2008;26:626-632.

  21. EORTC 62005 Studies and Intergroup S0033: PFS (Primary End Point) EORTC 62005 Study1 (N = 946) North American Intergroup S0033 Study2 (N = 694) Adapted with permission from Blanke CD et al. J Clin Oncol. 2008;26:626-632. Adapted with permission from Verweij J et al. Lancet. 2004;364:1127-1134. 1. Verweij J et al. Lancet. 2004;364:1127-1134. 2. Blanke CD et al. J Clin Oncol. 2008;26:626-632.

  22. MetaGIST: Overall PFS Advantage Among Patients Treated With Imatinib 800 mg/d in Phase 3 Trials 45-Month Follow-up Adapted with permission from Van Glabbeke MM et al. J Clin Oncol. 2007;25(18S):546s. Abstract 10004.

  23. Monitoring GIST and Assessing Response to Treatment

  24. CT Imaging of Advanced Disease 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 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 • Choi H. Curr Oncol Rep. 2005;7:307-311. • LeCesne A et al. J Clin Oncol. 2006;24(suppl):522s. Abstract 9510. 3. Blanke CD et al. J Clin Oncol. 2008;26:620-625.

  27. RECIST Did Not Predict Outcome in a Phase 3 Imatinib Trial (62005) 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 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;25:1753-1759.

  29. Choi et al: Modified CT Response Evaluation Criteria aSum of the longest diameters of target lesions as defined in RECIST. Adapted with permission from Choi H et al. J Clin Oncol. 2007;25:1753-1759.

  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

  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 CML, chronic myeloid leukemia; IV, intravenous. 1. Van Glabbeke M et al. Eur J Cancer. 2006;42:2277-2285. 2. Blay JY et al. J Clin Oncol. 2007;25:1107-1113. 3. Partridge AH et al. J Natl Cancer Inst. 2002;94:652-661. 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 1. Glivec [summary of product characteristics]. Novartis Pharma AG; 2007. 2. Verweij J et al. Eur J Cancer. 2003;39:2006-2011. 3. Blanke C et al. 2004 Gastrointestinal Cancers Symposium. Abstract 2. 4. Perik PJ et al. Ann Oncol. 2008:19:359-361.

  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%) 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;26:626-632. 3. Verweij J et al. Lancet. 2004;364:1127-1134. 4. Van Glabbeke M et al. Eur J Cancer. 2006;42:2277-2285.

  35. Management of AEs 1. Guilhot F. Oncologist. 2004;9:271-281. 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 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 von Mehren M et al. Hematol Oncol Clin North Am. 2005;19:547-564.

  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 PK, pharmacokinetics; TPC, trough plasma concentration. Demetri GD et. al Presented at: 2008 ASCO Gastrointestinal Cancers Symposium; 2008. Abstract 3.

  40. Pivotal Phase 2 Trial: Higher Imatinib Trough Plasma Level Correlates With Clinical Benefit Imatinib TPC Quartiles Overall Objective Clinical Benefit by Imatinib TPC Quartiles 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; 2008. Abstract 4523.

  41. Time to Progression in Patients With Imatinib PK by Cmin Quartiles Cmin, minimum concentration. Adapted with permission from Demetri GD et al. Presented at: ASCO Gastrointestinal Cancers Symposium; 2008. Abstract 3.

  42. Primary and Secondary Resistance: Definition 1. von Mehren M et al. Hematol Oncol Clin North Am. 2005;19:547-564. 2. Blay JY et al. Ann Oncol. 2005;16:566-578.

  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 1. Chen LL et al. Curr Oncol Rep. 2005;7:293-299. 2. Heinrich MC et al. J Clin Oncol. 2006;24:4764-4774. 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 AI, assessment inadequate. 1. Zalcberg JR et al. Eur J Cancer. 2005;41:1751-1757. 2. Blanke CD et al. J Clin Oncol. 2008:26:626-632.

  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 1. Zalcberg JR et al. Eur J Cancer. 2005;41:1751-1757. 2. Blanke CD et al. J Clin Oncol. 2008;26:626-632.3. 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 Conclusion:Continuation of imatinib is mandatory in recurrent and metastatic GIST. Imatinib may be used as an investigational adjuvant and neoadjuvant agent to surgeryin 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;16:566-578. 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 1. von Mehren M et al. Hematol Oncol Clin North Am. 2005;19:547-564. 2. Blanke CD et al. J Clin Oncol. 2008;26:626-632.

  48. Imatinib Treatment for Adjuvant GIST

  49. 713 patients randomized 97 discontinued treatment early 87 discontinued treatment early 30 events 5 GIST-unrelated deaths ACOSOG Z9001: Trial Schema Imatinib (359 randomized) (337 treated) IM 400 mg/day or placebo for 1 yr (Phase III) 778 patients 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  IM400 mg/d; or If IM 400 mg/d  IM800 mg/d

  50. Patient characteristics

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