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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.

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Presentation on theme: "1 GIST Overview. 2 GIST: Definition Mesenchymal (connective tissue) neoplasms Located primarily in the GI tract, omentum, and mesentery 0.2% of all GI."— Presentation transcript:

1 1 GIST Overview

2 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: Miettinen M et al. Arch Pathol Lab Med. 2006;130:

3 3 GIST: Incidence 1. Miettinen M et al. Virchows Arch. 2001;438: Fletcher CDM et al. Hum Pathol. 2002;33: Goettsch WG et al. Eur J Cancer. 2005;41: Nilsson B et al. Cancer. 2005;103: An estimated 10 to 20 cases of GIST per million persons are diagnosed in the United States each year 1 –5000 to 6000 cases per year are diagnosed in the United States 2 Incidence in Europe 3-7 is estimated between 6.6 and 14.5 cases per million Highest incidence among group aged 50 to 65 years 1 –Similar male/female incidence, although some reports suggest higher incidence in men Prevalence in Sweden: 129 cases per million 4 5. Tryggvason G et al. Int J Cancer. 2005;117: Rubio J et al. Eur J Cancer. 2007;43: Mucciarini C et al. BMC Cancer. 2007;7:230.

4 4 GIST: Clinical Presentation Most patients present with nausea, vomiting, pain, weight loss, palpable tumor masses, and bleeding leading to anemia 2 Average duration of presenting symptoms is 4 to 6 months 2 1. Miettinen M et al. Hum Pathol. 1999;30: Ghanem N et al. Eur Radiol. 2003;13: Symptoms of GIST at Diagnosis 1 SymptomOccurrence Rate Abdominal pain50%-70% GI bleeding50%

5 5 Circumstances of GIST Detection Incidental Symptomatic Autopsy 69% 21% 10% 1.Kindblom LG. vgnextoid=8a7ca1f VgnVCM100000f2730ad1RCRD&spk=Kindblom%2C+Lars-Gunnar+%5Bfau%5D. 2.Miettinen M et al. Hum Pathol. 1999;30: Approximately one-third of GISTs are asymptomatic 1,2

6 6 Common Tumor Sites 1. Corless CL et al. Annu Rev Pathol. 2008;3: Colon, rectum, esophagus, mesentery, omentum 60% 15% 25% Small intestine Stomach GIST may arise anywhere along the GI tract or elsewhere in the abdomen or retroperitoneum 1

7 7 KIT and PDGFR  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 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: Corless CLet al. Annu Rev Pathol. 2008;3:

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

9 9 Normal Biologic Function of KIT Receptor Tyrosine Kinase 1. Taylor ML et al. Hematol Oncol Clin North Am. 2000;14: Beghini A et al. Cancer. 2001;92: KIT plays an essential role 1,2 in Activation of KIT is critical in cell functions, including 1 Hematopoiesis Proliferation Skin pigment Differentiation Fertility Apoptosis/survival Gut motility (pacemaker cells) Adhesion/chemotaxis

10 10 KIT Mutations Up to 95% GISTs stained positive for KIT 1 –A subset (2% to 5%) of GIST stain negative for KIT expression 2 Mutant forms of KIT are constitutively active 3 Knock-in mice studies with KIT mutations showed 4 –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 population 5-7 –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: Heinrich CM et al. J Clin Oncol. In press. 3. Hirota S et al. Science. 1998;279: Sommer G et al. Proc Natl Acad Sci U S A. 2003;100: Agaimy A et al. Am J Surg Pathol. 2007;31: Kawanowa K et al. Hum Pathol. 2006;37: Abraham SC et al. Am J Surg Pathol. 2007;31:

11 11 Histopathology 1. Fletcher CD et al. Hum Pathol. 2002;33: Corless CL et al. Annu Rev Pathol. 2008;3: GISTs range in size from 1 to 40 cm (average ~5 cm) 2 GIST can be classified into 3 broad categories 1 –Spindle-cell type (70%) –Epithelioid-cell type (20%) –Mixed spindle-cell and epithelioid-cell type (nested morphology) (10%) Spindle cell Epithelioid cellMixed morphology 1

12 12 Imatinib Treatment for Unresectable or Metastatic GIST

13 13 Algorithm: Imatinib Treatment in Unresectable or Metastatic GIST 1,2 OR, overall response; RFA, radiofrequency ablation; SD, stable disease. 1. Reichardt P. EJC Suppl. 2006;4(suppl 1): NCCN. Clinical practice guidelines. Soft tissue sarcoma. V Demetri GD et al. J Natl Compr Canc Netw. 2007;5(suppl 2):S1-S29. Progression Metastatic KIT exon 9+ Imatinib 800 mg/d Dose-escalate Imatinib 800 mg/d Metastatic Imatinib 400 mg/d Unresectable Imatinib 400 mg/d OR or SD Secondary surgery Continue imatinib OR or SD Continue imatinib OR or SD Continue imatinib 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) Limited/Local Generalized/ Systemic

14 14 Imatinib in GIST: Rationale 1. Manley PW et al. Eur J Cancer. 2002;38(suppl 5):S19-S Heinrich MC et al. Hum Pathol. 2002;33: As a specific inhibitor of tyrosine kinase activity, imatinib blocks kinase-mediated downstream signaling 1 Mutations ~90% of GIST harbor mutations in KIT or PDGFRA genes 2 Mutations occur early in the development of GIST 1,2 –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 GIST 1

15 15 Inhibition of KIT Signaling by Imatinib P PPP ATP SIGNALING Imatinib mesylate Kinase domains 1. Savage DG et al. N Engl J Med. 2002;346: Scheijen B et al. Oncogene. 2002;21: The ATP binding pocket of the KIT kinase domain is occupied by imatinib 1 Substrate phosphorylation is prevented and signaling is inhibited 1 With signaling inhibited, proliferation and survival are interrupted 1,2

16 16 Pivotal Phase 2 Trial: Design PD Continue to treat as long as patient benefits and drug-related safety concerns are absent Imatinib (400 mg/d) Imatinib (600 mg/d) CT, computed tomography; MRI, magnetic resonance imaging. Demetri GD et al. N Engl J Med. 2002;347: Metastatic or unresectable GIST (N = 147) Imaging was performed with CT scanning or MRI PET imaging was performed at the discretion of the investigator

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

18 18 Pivotal Phase 2 Trial: Kaplan-Meier Estimate of OS Since Start of Study by Best Response 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: B2222 Study (63 Months’ Median Follow-up)

19 19 Pivotal Phase 2 Trial: Summary 147 patients randomized to 400 or 600 mg/d 1 At 5-year follow-up, 84% of patients showed clinical benefit 2 –68% PR or CR –16% SD Median TTP was 2 years 2 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-up 3 Maintenance of imatinib plasma trough levels (C min ) above 1110 ng/ mL is associated with best rates of clinical benefit and longest TTP 4 SWOG, Southwest Oncology Group; TTP, time to progression. 1. Demetri GD et al. N Engl J Med. 2002;347: Blanke CD et al. J Clin Oncol. 2008;26: Blanke C et al. ASCO Gastrointestinal Cancers Symposium; Abstract Demetri GD et al. ASCO Gastrointestinal Cancers Symposium; Abstract 3.

20 20 Phase 3 Trials: Design Follow for PFS Imatinib (400 mg/d) Imatinib (800 mg/d) PD 1. Verweij J et al. Lancet. 2004;364: Blanke CD et al. J Clin Oncol. 2008;26: Metastatic or unresectable GIST EORTC/ISG/AGITG Study North American Intergroup Study S0033 2

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

22 22 MetaGIST: Overall PFS Advantage Among Patients Treated With Imatinib 800 mg/d in Phase 3 Trials Median PFS, years 3 Years Estimated (Kaplan-Meier) 400 mg/d800 mg/d400 mg/d800 mg/dHRP value PFS All patients (N = 1640) %34% EORTC (N = 946) %35% SWOG 0033 (N = 649) %33% OS(N = 1640) %61% PFS According to KIT Exon 9 Mutation Status 400 mg/d800 mg/d400 mg/d800 mg/dHRP value All patients (N = 91) %17% EORTC (N = 59) %25% SWOG 0033 (N = 32) %6% Adapted with permission from Van Glabbeke MM et al. J Clin Oncol. 2007;25(18S):546s. Abstract Month Follow-up

23 23 Monitoring GIST and Assessing Response to Treatment

24 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 25 18 FDG-PET Imaging Images courtesy A.D. Van den Abbeele. Large hepatic metastasis Hepatic, abdominal, and pelvic metastases

26 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 bulk 1 Fluid expansion in responding necrotic GIST may result in increase in tumor size 1 Criteria do not capture change in tumor density 1 Criteria underestimate overall clinical benefit by not including stable disease in the evaluation 1,2 –Survival of patients with stable disease similar to that of patients with objective response (Study B2222) 3 1.Choi H. Curr Oncol Rep. 2005;7: LeCesne A et al. J Clin Oncol. 2006;24(suppl):522s. Abstract Blanke CD et al. J Clin Oncol. 2008;26:

27 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) CategoryTTP (y) 3-Year OS (%) TTP (y) 3-Year OS (%) TTP (y) 3-Year OS (%) CR/MR/PR responders NC+/NC– PD nonresponders 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 N = 906.

28 28 Choi et al: Proposal of Modified CT Response Criteria Choi H et al. J Clin Oncol. 2007;25: 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 18 FDG-PET responses a –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 18 FDG-PET scans –Multivariate analysis was carried out using tumor size and density (HU) on CT and SUV max on 18 FDG-PET –Patients followed for up to 28 months a Good response defined as a 70% decrease in SUV max to an absolute value of <2.5. HU, Hounsfield unit; SUV max, maximum standardized uptake value.

29 29 Choi et al: Modified CT Response Evaluation Criteria ResponseDefinition CR Disappearance of all lesions No new lesions PR A decrease in size a of ≥10% or a decrease in tumor density (HU) of ≥15% on CT No new lesions 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 a Sum 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 30 Summary: Monitoring GIST and Assessing Response to Treatment CT and 18 FDG-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) 18 FDG-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 – 18 FDG-PET as a tool to be used also in surveillance CT and 18 FDG-PET are useful in early recognition of the signs of PD –CT may be used to detect focal recurrence and clonal resistance – 18 FDG-PET effective in visualizing reactivated tumor cells when imatinib is withdrawn

31 31 Practical Management of Imatinib Therapy for GIST

32 32 Practical Management of Imatinib Therapy for GIST Management of AEs is key to compliance with therapy 1 Interruption of imatinib therapy often results in rapid tumor progression 2 Imatinib differs from IV chemotherapy –Oral daily administration –Typically taken for long periods of time Long-term adherence to oral cancer therapies problematic 3 Adherence with imatinib in CML shown to decline over time 4,5 CML, chronic myeloid leukemia; IV, intravenous. 1. Van Glabbeke M et al. Eur J Cancer. 2006;42: Blay JY et al. J Clin Oncol. 2007;25: Partridge AH et al. J Natl Cancer Inst. 2002;94: Tsang J et al. J Clin Oncol. 2006;24:330s. Abstract Feng W et al. J Clin Oncol. 2006;24:310s. Abstract 6038.

33 33 AE Profile of Imatinib in GIST Most patients taking imatinib experience AEs during therapy, but the drug is generally well tolerated 1,2 –AEs usually are mild to moderate –Few drug-related discontinuations in GIST trials AEs generally most troublesome in first 2 months of therapy 2 Rates of common AEs consistent over 4-year follow-up 3 Reports of cardiac adverse events are uncommon 1,4 1. Glivec [summary of product characteristics]. Novartis Pharma AG; Verweij J et al. Eur J Cancer. 2003;39: Blanke C et al Gastrointestinal Cancers Symposium. Abstract Perik PJ et al. Ann Oncol. 2008:19:

34 34 Imatinib 800 mg/d: Tolerability and Safety EORTC, European Organisation for Research and Treatment of Cancer; SAEs, serious adverse events. 1. Reichardt P. EJC Suppl. 2006;4(suppl 1): Blanke CD et al. J Clin Oncol. 2008;26: Verweij J et al. Lancet. 2004;364: Van Glabbeke M et al. Eur J Cancer. 2006;42: Phase 3 results demonstrate that doses up to 800 mg/d are generally well tolerated 1-3 –EORTC 62005: rates of SAEs similar in high- and low-dose groups (38% vs 37%, respectively) Toxicities dose dependent 4 Patients who dose-escalate from 400 to 800 mg/d appear to tolerate high dose better 2,4 –US-Finland S0033: SAEs more common with high vs low dose (63% vs 43%)

35 35 Management of AEs 1. Guilhot F. Oncologist. 2004;9: Demetri GD et al. J Natl Compr Canc Netw. 2004;2(suppl 1):S1-S Blay JY et al. Proc Am Soc Clin Oncol. 2004;23:815. Abstract Most AEs associated with imatinib therapy 1,2 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 interruption 2,3 Reinitiate therapy without dose reduction Interruption and subtherapeutic dosing may increase risk of progression and resistance

36 36 Managing Progressive Disease

37 37 Discontinuation of Imatinib Increases Risk of GIST Progression 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. 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

38 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:

39 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: C min <1110 ng/mL –Q2 + Q3: C min ≥1110 to <2040 ng/mL –Q4: C min ≥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; Abstract 3.

40 40 Pivotal Phase 2 Trial: Higher Imatinib Trough Plasma Level Correlates With Clinical Benefit Q1 (n = 18) Q2-Q3 Combined Q4 (n = 19) Q2 (n = 18)Q3 (n = 18) Mean, ng/mL797 ± ± ± ± 530 CV, % Range Imatinib TPC Quartiles Response n (%) Q1 (n = 18) Q2-Q3 (n = 36) Q4 (n = 19) CR + PR + SD12 (67)29 (81)16 (84) PD/unknown6 (33)7 (19)3 (16) 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; Abstract 4523.

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

42 42 Primary and Secondary Resistance: Definition 1. von Mehren M et al. Hematol Oncol Clin North Am. 2005;19: Blay JY et al. Ann Oncol. 2005;16: Primary Resistance 1,2 (no response) Secondary (Acquired) Resistance 1,2 (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

43 43 Mechanisms of Mutational Resistance to Imatinib (cont’d) Overexpression or amplification of KIT or PDGFRA gene 1-3 Activation of downstream signal pathways bypassing KIT 1-3 P-glycoprotein overexpression 1 Antiapoptosis 1 Decrease in imatinib intracellularly due to increased metabolism (eg, p450,  -1 acid glycoprotein) 1 1. Chen LL et al. Curr Oncol Rep. 2005;7: Heinrich MC et al. J Clin Oncol. 2006;24: Fletcher JA et al. Proc Am Soc Clin Oncol. 2003;22:815. Abstract 3275.

44 44 Phase 3 Studies: Response Rates After Crossover to Imatinib 800 mg/d AI, assessment inadequate. 1. Zalcberg JR et al. Eur J Cancer. 2005;41: Blanke CD et al. J Clin Oncol. 2008:26: Trial 1 S0033 Trial 2 One-third of patients benefited from dose increase at progression

45 45 Imatinib Dose Optimizing in GIST Phase 3 studies have demonstrated the feasibility of dose escalation in PD 1,2 Approximately one-third of patients with PD achieve clinical benefit (objective response or stable disease) after dose increase 1,2 Available safety data suggest that dose escalation to 800 mg/d has no adverse effect on safety and tolerability 3 1. Zalcberg JR et al. Eur J Cancer. 2005;41: Blanke CD et al. J Clin Oncol. 2008;26: Glivec [summary of product characteristics]. Novartis Pharma AG; 2007.

46 46 Use of Surgery and Imatinib Therapy in Recurrent Disease Recurrent GIST should be managed as metastatic disease and treated with imatinib 1-3 Imatinib therapy may be complemented by surgical resection –Provides survival benefit with continued use of imatinib 4 –May provide a survival benefit even in imatinib-resistant patients 5 –Recommended for isolated clonal progression 1 1. Demetri GD et al. J Natl Compr Canc Netw. 2007;5(suppl 2):S1-S Blay JY et al. Ann Oncol. 2005;16: Casali PG et al. Ann Oncol. 2008;19(suppl 2):ii35-ii Hohenberger P et al. J Clin Oncol. 2006;24(suppl):520s. Abstract Nishida T et al. J Clin Oncol. 2006;24(suppl):531s. Abstract 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 disease 1-5

47 47 Progressive GIST: When to Consider a Second-Line Agent Steps to take to clarify cause of resistance 1 –Verify imatinib compliance and check blood level –Identify possible pharmacokinetic factors Continue imatinib therapy: effective KIT/PDGFRA suppression must be maintained 1 Use of second-line inhibitor therapy 1 –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: Blanke CD et al. J Clin Oncol. 2008;26:

48 48 Imatinib Treatment for Adjuvant GIST

49 49 ACOSOG Z9001: Trial Schema (Phase III) 778 patients Placebo (354 randomized) (345 treated) 87 discontinued treatment early Imatinib (359 randomized) (337 treated) 97 discontinued treatment early 30 events 5 GIST-unrelated deaths 713 patients randomized 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 IM 400 mg/day or placebo for 1 yr 70 events 5 GIST-related deaths 3 GIST-unrelated deaths

50 50 Parameters Placebo (n=354) Imatinib (n=359) Age, median (range)58 (18-91)59 (18-88) Gender, n (%) Female163 (46.0%)189 (52.6%) Male191 (54.0%)170 (47.4%) Performance Status, n (%) 0265 (74.9%)281 (78.3%) 181 (22.9%)74 (20.6%) 28 (2.3%)4 (1.1%) Days between resection & randomization; median (range) 59 (15-96)57 (20-74) Patient characteristics

51 51 Parameters Placebo (n=354) Imatinib (n=359) Tumor size, n (%) >3 and <6 cm149 (42.1%)143 (39.8%) >6 and <10 cm119 (33.6%)123 (34.3%) >10 cm86 (24.3%)93 (25.9%) Margins, n (%) R0330 (93.2%)325 (90.5%) R123 (6.5%)34 (9.5%) Unknown1 (0.3%)0 (0.0%) Tumor origin, n (%) Stomach235 (66.4%)209 (58.2%) Small intestine102 (28.8%)125 (34.8%) Rectum5 (1.4%) Other12 (3.4%)18 (5.0%) Unknown0 (0.0%)2 (0.6%) R0 – negative microscopic margins; R1 – positive microscopic margins Patient characteristics (continued)

52 52 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 Events experienced: Imatinib: 8.0% (30) Placebo: 20.0% (70) Recurrence-free Survival (RFS)* *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).

53 53 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 Recurrence-free Survival (Tumor size) size >10cm size >3 and <6 cm size >6cm and <10cm

54 54 No difference in OS between imatinib and placebo adjuvant therapies Longer follow-up might reveal a longer OS Overall Survival (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).

55 55  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 < ) Reduction / interruption of treatment Placebo (n=354) 345 received treatment 9 did not receive treatment 33 ineligible patients Grade 3 or 4 AEs: 31.0% (n=104) Grade 3 or 4 AEs: 18.0% (n=63) 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 Imatinib (n=359) 337 received treatment 22 did not receive treatment 32 ineligible patients 713 patients randomized

56 56 Safety / Tolerability Adverse Event Placebo (n=345) Imatinib (n=337) Grade 3Grade 4Grade 3Grade 4 Neutropenia3 (<1%)1 (<1%)7 (2%)5 (1%) Fatigue4 (1%)05 (1%)2 (<1%) Dermatitis0011 (3%)0 Abdominal pain6 (1%)012 (3%)0 Nausea4 (1%)08 (2%)0 Vomiting2 (<1%)08 (2%)0 Diarrhea5 (1%)010 (2%)0 ALT007 (2%)2 (<1%) AST004 (1%)3 (<1%) Edema1 (<1%)07 (2%)0 Hyperglycemia7 (2%)02 (<1%)0 Hypokalemia3 (<1%)04 (1%)0 Syncope004 (1%)0 Dyspnea2 (<1%)04 (1%)0 ALT, alanine aminotransferase; AST, aspartate aminotransferase

57 57 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 Summary


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