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

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.

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

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

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.

Symptoms of GIST at Diagnosis1

Symptom Occurrence Rate

Abdominal pain 50%-70%

GI bleeding 50%

5

Circumstances of GIST Detection

Incidental

Symptomatic

Autopsy

69%21%

10%

1. Kindblom LG. http://www.asco.org/portal/site/ASCO/menuitem.d3934b88626d03a781d54d10ee37a01d/?vgnextoid=8a7ca1f903878010VgnVCM100000f2730ad1RCRD&spk=Kindblom%2C+Lars-Gunnar+%5Bfau%5D.

2. Miettinen M et al. Hum Pathol. 1999;30:1213-1220.

Approximately one-third of GISTs are asymptomatic1,2

6

Common Tumor Sites

1. Corless CL et al. Annu Rev Pathol. 2008;3:557-586.

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 retroperitoneum1

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 kinasedomains

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.

Normal KIT Signaling

PP P

ADP P

P

PP P

ATP

SIGNALING

Kinasedomains

Substrate

Effector

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.

Activation of the substrate initiates a signaling cascade,

culminating in cell proliferation and survival1,2

A substrate protein (eg, PI3 kinase) is phosphorylated by KIT kinase1,2

9

Normal Biologic Function of KIT Receptor Tyrosine Kinase

1. Taylor ML et al. Hematol Oncol Clin North Am. 2000;14:517-535. 2. Beghini A et al. Cancer. 2001;92:657-662.

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

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

1. Fletcher CD et al. Hum Pathol. 2002;33:459-456.2.Corless CL et al. Annu Rev Pathol. 2008;3:557-586.

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

12

Imatinib Treatment for Unresectable or Metastatic GIST

13

Algorithm: Imatinib Treatment in Unresectable or Metastatic GIST1,2

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.

Progression

Progression

MetastaticKIT exon 9+

Imatinib 800 mg/d

Dose-escalateImatinib 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

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.

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

15

Inhibition of KIT Signaling by Imatinib

P

PP P

ATP

SIGNALING

Imatinib mesylate

Kinasedomains

1. Savage DG et al. N Engl J Med. 2002;346:683-693.2. Scheijen B et al. Oncogene. 2002;21:3314-3333.

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

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;347:472-480.

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

03

6965

1418

0

10

20

30

40

50

60

70

Pat

ien

ts,

%

Pivotal Phase 2 Trial: Best Observed Rates of Response to Imatinib

CR, complete response.

Blanke CD et al. J Clin Oncol. 2008;26:620-625.

Tumor Control

63 Months’ Median Follow-up2

400 mg/d (n = 73)

600 mg/d (n = 74)

PR SD CR PR SDCR

Based on Slide 53 from IM TX deck

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;26:620-625.

B2222 Study (63 Months’ Median Follow-up)

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

Followfor

PFS

Imatinib(400 mg/d)

Imatinib(800 mg/d)

PD

1. Verweij J et al. Lancet. 2004;364:1127-1134.2. Blanke CD et al. J Clin Oncol. 2008;26:626-632.

Metastatic or unresectable

GIST

EORTC/ISG/AGITG Study 620051

North American Intergroup Study S00332

21

EORTC 62005 Studies and Intergroup S0033: PFS (Primary End Point)

1. Verweij J et al. Lancet. 2004;364:1127-1134. 2. Blanke CD et al. J Clin Oncol. 2008;26:626-632.

EORTC 62005 Study1

(N = 946)North American Intergroup

S0033 Study2 (N = 694)

Adapted with permission from Verweij J et al. Lancet. 2004;364:1127-1134.

Adapted with permission from 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

Median PFS, years3 Years Estimated

(Kaplan-Meier)

400 mg/d 800 mg/d 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% 0.89 0.12

SWOG 0033 (N = 649)

1.46 1.64 29% 33% 0.89 0.18

OS (N = 1640) 4.08 4.05 60% 61% 1.00 0.97

PFS According to KIT Exon 9 Mutation Status

400 mg/d 800 mg/d 400 mg/d 800 mg/d HR P value

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 0.97

Adapted with permission from Van Glabbeke MM et al. J Clin Oncol. 2007;25(18S):546s. Abstract 10004.

45-Month Follow-up

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

Images courtesy A.D. Van den Abbeele.

Large hepatic metastasis Hepatic, abdominal, and pelvic metastases

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

1. Choi H. Curr Oncol Rep. 2005;7:307-311. 2. 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)

2 Months(n = 852)

4 Months(n = 681)

6 Months(n = 642)

Category TTP (y)

3-Year OS (%)

TTP (y)

3-Year OS (%)

TTP (y)

3-Year OS (%)

CR/MR/PRresponders

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

PDnonresponders

0.15 13.6 0.31 25.6 0.48 19.7

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.

N = 906.

28

Choi et al: Proposal of Modified CT Response Criteria

Choi H et al. J Clin Oncol. 2007;25:1753-1759.

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.

29

Choi et al: Modified CT Response Evaluation Criteria

Response 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 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

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

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.

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%)

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.

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

36

Managing Progressive Disease

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

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

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 410-1110 1110-1390 1390-2040 2040-4180

Imatinib TPC Quartiles

Responsen (%)

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)

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.

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

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 Phase 3 Studies: Response Rates After Crossover to Imatinib 800 mg/dCrossover to Imatinib 800 mg/d

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.

62005 Trial1 S0033 Trial2

One-third of patients benefited from dose increase at progression

0 2

27

59

10

10

20

30

40

50

60

70

CR PR SD PD AI

Pat

ien

ts, %

3

42

22

1015

0

10

20

30

40

50

60

70

CR PR SD PD AI

Pat

ien

ts, %

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

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.

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

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

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

ParametersPlacebo(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 (%)

0 265 (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)

Patient characteristics

51

ParametersPlacebo(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%) 5 (1.4%)

Other 12 (3.4%) 18 (5.0%)

Unknown 0 (0.0%) 2 (0.6%)R0 – negative microscopic margins; R1 – positive microscopic margins

Patient characteristics (continued)

52

Median follow-up: 19.7 months

Estimated 1-year RFS (95% CI):

Imatinib: 98% (96-100)Placebo: 83% (78-88)

HR = 0.35 (0.22-0.53)P < 0.0001

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 frompatient 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

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

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).

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184 (26%) patients discontinued therapy; the main reasons included :

– Adverse events (AEs): imatinib (n=57) vs. placebo (n=11) (P < 0.0001) – Tumor recurrence: imatinib (n=1) vs. placebo (n=41) (P < 0.0001)

Reduction / interruption of treatment

Placebo (n=354)345 received treatment

9 did not receive treatment33 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 early57 (15.9%) for adverse events1 (<1%) for disease recurrence15 (4.2%) for patient withdrawal

24 (6.7%) for other/missing reasons

87 (24.6%) discontinued treatment early11 (3.1%) for adverse events

41 (11.6%) for disease recurrence20 (5.6%) for patient withdrawal

15 (4.2%) for other/missing reasons

Imatinib (n=359)337 received treatment

22 did not receive treatment32 ineligible patients

713 patientsrandomized

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Safety / Tolerability

Adverse Event

Placebo(n=345)

Imatinib(n=337)

Grade 3 Grade 4 Grade 3 Grade 4

Neutropenia 3 (<1%) 1 (<1%) 7 (2%) 5 (1%)

Fatigue 4 (1%) 0 5 (1%) 2 (<1%)

Dermatitis 0 0 11 (3%) 0

Abdominal pain 6 (1%) 0 12 (3%) 0

Nausea 4 (1%) 0 8 (2%) 0

Vomiting 2 (<1%) 0 8 (2%) 0

Diarrhea 5 (1%) 0 10 (2%) 0

ALT 0 0 7 (2%) 2 (<1%)

AST 0 0 4 (1%) 3 (<1%)

Edema 1 (<1%) 0 7 (2%) 0

Hyperglycemia 7 (2%) 0 2 (<1%) 0

Hypokalemia 3 (<1%) 0 4 (1%) 0

Syncope 0 0 4 (1%) 0

Dyspnea 2 (<1%) 0 4 (1%) 0

ALT, alanine aminotransferase; AST, aspartate aminotransferase

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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

Summary