Jon Trent, MD, PhD

1
Gastrointestinal Stromal Tumor Life Fest 2006
Jon Trent, MD, PhD Assistant Professor Dept. of
Sarcoma Medical Oncology The University of Texas,
M. D. Anderson Cancer Center jtrent_at_mdanderson.o
rg
www.ctos.org
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Background
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GIST Overview

• Most common GI sarcoma
• 0.2 of all GI tumors, but 80 of GI sarcomas
• Distinct clinical and histopathologic entity
• Highest incidence in the 40-60 year age group
• Similar male/female incidence
• Many misclassified as leiomyosarcoma
• GIST have an incidence of 14.5 per million
  annually and a prevalence of 129 per million
• Clinical presentation is variable
• pain, hemorrhage, anemia, anorexia, nausea,
  perforation

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Median Overall Survival in Metastatic GIST
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Chemotherapy TrialsAdvanced GIST
Number of Partial
Response Regimen Patients n () DOX
DTIC 43 3 (7) DOX DTIC / IF 60 10
(15) IF VP-16 10 0 (0) Paclitaxel 15 1
(7) Gemcitabine 17 0 (0) Liposomal
DOX 15 0 (0) DOX 12 0 (0) DOX or
docetaxel 9 0 (0) High-dose IF 26 0
(0) EPI IF 13 0 (0) Various 40 4
(10) DTIC/MMC/DOX/ CDDP/GMCSF 21 1
(5) Temozolamide 19 0 (0) TOTAL 280 19
(6.8)
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GIST Overview

• GIST share several characteristics with ICC
• Neuromuscular pacemaker cell of the GI tract
• Found in myenteric plexus throughout GI tract
• Expression of CD34 in 80 of cases
• Expression of KIT (CD117) in 95 of cases

ICC interstitial cells of Cajal. Corless et al.
J Clin Oncol. 2004223813. Sircar et al. Am J
Surg Pathol. 199923377.
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Kit Receptor Structure
Extracellular Domain (exon 9, 10.2)
Juxtamembrane Domain (exon 11, 66.1)
ATP
Tyrosine Kinase Domain I (exon 13/14, 1.2)
Tyrosine Kinase Domain II (exon 17, 0.6)
common mutation site
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Kit Receptor Phenotype
ADP P
ATP
Proliferation Survival Adhesion Invasion Metastasi
s Angiogenesis
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Imatinib Mesylate
Formula C30H35N7SO4 MW 589.7
Inhibitor of selective tyrosine
kinases bcr-abl PDGF-R c-kit

• Rational drug design
• 2-phenylamino pyrimidine
• Based on structure of ATP binding site
• Highly water soluble
• Oral bioavailability

Potent (IC50 ? 0.1?M)
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Kit Receptor Phenotype
ATP
Imatinib
Proliferation Survival Adhesion Invasion Metastasi
s Angiogenesis
imanitib contact point
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(No Transcript)
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The First GIST Patient Histology
HE (at diagnosis) HE Ki 67 CD117
One month of therapy
Pretreatment
Joensuu H et al. N Engl J Med. 20013441052-1056.
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What is the chance of imatinib helping me?
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Clinical Trials of Imatinib in GIST
Study Phase N OR CR PR SD PD OS (2 yr) TTP (median) PFS
van Oosterom, 2001 I 36 53 0 53 36 11 - - -
von Mehren, 2002 II 147 63 0 63 19 12 - 72 wks -
Verweij, 2003 II 27 71 4 67 18 11 - - 73 (1 yr)
Rankin, 2004 III 746
-400 mg daily 48 3 45 - - 78 - 50 (2 yr)
-800 mg daily 48 3 45 - - 73 - 53 (2 yr)
Verweij, 2004 III 946
-400 mg daily 50 5 45 32 13 69 - 44 (2 yr)
-800 mg daily 54 6 48 32 9 74 - 52 (2 yr)
Courtesy Dejka Steinert, M.D.
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Phase III dose-randomized study of Imatinib
mesylate (Gleevec, STI571) for GIST NA
Intergroup S0033 early results. Robert S.
Benjamin, UT MD Anderson Cancer Center and SWOG,
Houston, TX, Cathryn Rankin, SWOG, Christopher
Fletcher, Dana Farber Cancer Institute, Charles
Blanke, SWOG, Margaret von Mehren, ECOG, Robert
Maki, CALGB, Vivien Bramwell, NCIC, Laurence
Baker, SWOG, Ernest Borden, SWOG, George D.
Demetri, Dana Farber Cancer Institute, CALGB, as
the North American Sarcoma Intergroup
Benjamin et al, ASCO 2003
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North American Sarcoma Intergroup Schema
C R O S S O V E R
R A N D O M I Z A T I O N
Low Dose Imatinib 400 mg/d
High Dose Imatinib
Off Protocol Treatment
Progression
Progression
High Dose Imatinib 800 mg/d
Progression
Off Protocol Treatment
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EORTC Phase III Imatinib for Advanced
GISTSurvival Benefit
Verweij, et al 2004
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How long do I take imatinib?
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The First GIST Patient Histology
HE (at diagnosis) HE Ki 67 CD117
One month of therapy
Pretreatment
Joensuu H et al. N Engl J Med. 20013441052-1056.
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Phase III Trial US Intergroup S0033 Time to
Progression on Crossover
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Time to Tumor Progression
100 90 80 70 60 50 40 30 20 10 0
Sunitinib (N207)Placebo (N105)
Hazard ratio 0.335Plt0.00001
Median (95 CI)6.3 (3.7, 7.6)1.5 (1.0, 2.3)
Estimated TTP probability ()
0 3 6 9 12
Time (Months)
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Discontinuation of Imatinib Increases the Risk of
Progression (BFR14)
100
Continuous therapy (n23)
80
P0.0001
60
of patients
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Stop therapy (n25) Median PFS 6 months
20
0
16
14
12
10
8
6
4
2
0
Months after randomization

• Patients who achieved clinical benefit after 12
  months were randomized to continue or to stop
  imatinib mesylate therapy
• Randomization has been suspended

Blay et al. Proc Am Soc Clin Oncol. 200423815.
Abstract 9006.
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What dose of imatinib should I take?
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EORTC Phase III Imatinib for Advanced
GISTProgression-free Survival Benefit
Verweij, et al 2004
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Progression-free Survival By Imatinib Dose
Kit Exon 11 Mutation
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Progression-free Survival By Imatinib Dose
Kit Exon 9 Mutation
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Kit Mutation in GISTBenefit from 800mg Imatinib
Odds Ratio P-value
Exon 11 (n211) 1.0 0.96
Exon 9 (n25) 8.0 0.03
Wild-type (n33) 1.5 0.62
Heinrich et al, ASCO 2050
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Tell me about the side effects..
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Side effects 400 vs. 800 mg
Toxic Event Adjusted p-Value
Edema lt0.001
Anemia lt0.001
Rash lt0.001
Fatigue lt0.001
Nausea lt0.001
Hemorrhage lt0.001
Diarrhea 0.0026
Dyspnea 0.036
Pleuritic Pain 0.053
Verweij et al, 2004
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Interruptions and Reductions of Therapy
400 mg 800 mg
Treatment Interruption 40 64
-Hematologic 6 7
-Non-Heme 23 43
Dose Reduction 16 60
-Hematologic 2 4
-Non-heme 10 42
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North American Intergroup Phase III Study of
Imatinib in Advanced GIST
Dose Reduction 400 mg (376 pts) 800 mg (370 pts) 800 mg X-Over
1 10 44 16
2 7 26 5
3 2 11 0
4 1 4 0
Dileo et al, ASCO 2005
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How do I know if imatinib is working?
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Confirmed Overall Responses with Gleevec
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Best Response (B222)
400 mg N73 n () 600 mg N74 n () All Patients N147 n ()
Complete Response 0 2 (2.7) 2 (1.4)
Partial Response 50 (68.5) 48(64.9) 98 (66.7)
Stable Disease 10 (13.7) 13 (17.6) 23 (15.6)
Progression 11 (15.1) 6 (8.1) 17 (11.6)
Not evaluable 2 (2.7) 5 (6.8) 7 (4.8)
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Time to PR by RECIST
Cumulative incidence of CT responses
2 Months
1
0.9
0.8
3 Months
0.7
6 Months
0.6
0.5
CI
0.4
0.3
400 mg
800 mg
0.2
0.1
0
0
0.5
1
1.5
2
Years
Verweij et al, ASCO 2003
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CT Scan Results
Jun 27, 2000
Oct 4, 2000
Before Imatinib
After Imatinib
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Background (cont)
Decrease in GIST intravenous contrast uptake
after patient is treated for 8 weeks with
imatinib mesylate
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Overall Survival by Best Response(B222, Kaplan
Meier Estimate)
SD (n23) Median n/a
PD (n17) Median 36 wks
PR (n98) Median 248 wks
CR (n2 median OS n/a) and unknown/NE (n7
median OS 144 wks) not included
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Effects of Imatinib on GISTCT and PET findings
1/18
3/23
1/26
3/22
10/8
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Pseudoprogression Early During Treatment With
Imatinib Mesylate
Choi et al. AJR Am J Roentgenol. 20041831619.
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Effects of Imatinib on GISTCT findings
1/12
3/30
5/24
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Modified RECIST for GISTCT Size Density (Choi)

• Tumor size decrease of gt10 or tumor density
  decrease of gt15 were highly correlated with
  decrease in SUV by gt70 to a value lt2.5 on PET.
• RECIST criteria substantially underestimate, at
  least initially, the value of therapy with
  imatinib for GIST.

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What is genotyping?
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Kit Receptor Structure
Extracellular Domain (exon 9, 10.2)
Juxtamembrane Domain (exon 11, 66.1)
ATP
Tyrosine Kinase Domain I (exon 13/14, 1.2)
Tyrosine Kinase Domain II (exon 17, 0.6)
common mutation site
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Kit Mutation in GISTResponse to Imatinib (n332)
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Overall Survival by Genotype(B222, Kaplan Meier
Estimate)
Median Survival Median Survival
Exon 11 Not reached
Exon 9 1347 days (192 wks)
No mut 250 days (36 wks)
Exon 11
Exon 9
No Mutation
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Kit-Negative GIST
IHC Result PFS (2 year) OS (2 year)
Kit-negative GIST 43 57
Kit-expressing GIST 49 77
P-value NS 0.01
Blackstein et al, ASCO 2005
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How will you know whether my GIST comes back?
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Type of Progression
Limited progression
Nodular progression
Stable disease
Widespread progression
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Limited Progression
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Resistance to Imatinib Mesylate Recognition of
Clonal Evolution
Courtesy of Dr. G.D. Demetri.
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Secondary Mutation
Heinrich et al, JCO 2006
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What do I do if my GIST is resistant to imatinib?
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Therapy by Type of Progression

• Limited or Nodular Progression
• Hepatic Artery Embolization
• Hepatic Radio-frequency Catheter Ablation
• Surgical Resection
• Widespread progression
• Increase Imatinib to 800 mg daily
• Sunitinib
• Clinical Trial

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Hepatic Artery Embolization
Pre- embolization
Post- embolization
Courtesy of Dr. R. DeMatteo.
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Metastatic GIST Trials

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

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SU11248 in Advanced GISTSunitinib Malate, Sutent
Stop imatinib4 weeks
R A N D O M I Z E
SU11248 (207)
PD
PD on imatinib
6 weeks
Off
PD
Placebo (105)
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SU11248 in Advanced GISTObjective Response Rates
Sunitinib Placebo Imatinib 800mg
PR 7 0 6
SD 58 50 32
SDgt 6 mo 19 0 ND
PD 20 39 48
NE 14 11 13
Escalation of imatinib from 400 mg to 800 mg
daily.
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Time to Tumor Progression
100 90 80 70 60 50 40 30 20 10 0
Sunitinib (N207)Placebo (N105)
Hazard ratio 0.335Plt0.00001
Median (95 CI)6.3 (3.7, 7.6)1.5 (1.0, 2.3)
Estimated TTP probability ()
0 3 6 9 12
Time (Months)
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Should I take imatinib after my GIST was removed?
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Survival of GIST Patients by Primary Tumor Size
DeMatteo et al, 2000
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Post-operative Imatinib Trials

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

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Preoperative Imatinib Trials

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

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Patient Characteristicsn13
Characteristic Value
Age (median) 52 (range 38-67)
Gender (M/F) 7/6
Primary Site of Tumor
- Stomach 6
- Small Intestine 5
- Colon 2
Duration of Imatinib
- 3 days 4
- 5 days 5
- 7 days 4
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Preoperative Imatinib ToxicityGrade 3/4
Toxicity Number of Patients (n13)
Nausea/emesis 2
Abdominal pain 1
GI Hemorrhage 1
Hypovolemia 1
None 11
Patients able to finish 1 year of therapy
7/9 Patients with recurrence 1
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PET Response at Day 5
Pre-imatinib Post-imatinib (Day 5)
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PET Response Datan12
3 Days 5 Days 7 Days Total
Responders 3 2 3 8
Non-responder 1 2 1 4
PET-CT imaging
Courtesy Homer Macapinlac, M. D.
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Apoptosis After Imatinib
5 days post-imatinib
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Effect of Imatinib on Apoptosis
Post-Imatinib (3 days of therapy)
Pre-Imatinib
Immunofluorescent TUNEL Assay
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Will my kids get GIST?
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Familial GIST
I
II
III
II
I
III
V
VI
VII
IV
VIII
II
III
I
IV
I
II
IV
III
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Gastrointestinal Stromal Tumors
A Paradigm of Targeted Anti-Tumor Therapy
Jon Trent, MD, PhD jtrent_at_mdanderson.org Dept.
of Sarcoma Medical Oncology The University of
Texas, M. D. Anderson Cancer Center