Jon Trent, MD, PhD
Assistant Professor
Dept. of Sarcoma Medical Oncology
The University of Texas,
M. D. Anderson Cancer Ce...
BackgroundBackground
GIST OverviewGIST Overview
 Most common GI sarcomaMost common GI sarcoma
 0.2% of all GI tumors, but 80% of GI sarcomas0...
Median Overall Survival in Metastatic GISTMedian Overall Survival in Metastatic GIST
Chemotherapy TrialsChemotherapy Trials
Advanced GISTAdvanced GIST
Number of Partial Response
Regimen Patients n (%)
DOX + ...
GIST OverviewGIST Overview
 GIST share several characteristics with ICCGIST share several characteristics with ICC
 Neur...
Extracellular Domain (exon 9, 10.2%)
Juxtamembrane Domain (exon 11, 66.1%)
Tyrosine Kinase Domain I (exon 13/14, 1.2%)
Tyr...
ATP
Proliferation
Survival
Adhesion
Invasion
Metastasis
Angiogenesis
ADP
+
P
Kit Receptor Phenotype
Formula: C30H35N7SO4
MW: 589.7
IImatinib Mesylatematinib Mesylate
CH3SO3H
N
N
N
NH NH
O
N
N
 Rational drug designRational...
ATP
= imanitib contact point
Proliferation
Survival
Adhesion
Invasion
Metastasis
Angiogenesis
Im
atinib
Kit Receptor Pheno...
Joensuu H et al. N Engl J Med. 2001;344:1052-1056.
Marked Biologic Response Revealed
by PET Scan
Multiple liver and upper ...
Pr et r eat ment
One mont h
of t her apy
H&E ( at
di agnos i s )
H&E
Ki 67
CD117
Joensuu H et al. N Engl J Med. 2001;344:1...
What is the chance of imatinibWhat is the chance of imatinib
helping me?helping me?
Clinical Trials ofClinical Trials of
Imatinib in GISTImatinib in GIST
Study Phase N OR CR PR SD PD
OS
(2 yr)
TTP
(median)
...
Phase III dose-randomized study of
Imatinib mesylate (Gleevec, STI571) for
GIST:
NA Intergroup S0033 early results.
Robert...
Low Dose
Imatinib
400 mg/d
High Dose
Imatinib
Progression Progression
Off Protocol
Treatment
C
R
O
S
S
O
V
E
R
High Dose
I...
Verweij, et al 2004
EORTC Phase III Imatinib forEORTC Phase III Imatinib for
Advanced GISTAdvanced GIST
Survival BenefitSu...
How long do I takeHow long do I take
imatinib?imatinib?
Pr et r eat ment One mont h
of t her apy
H&E ( at
di agnos i s )
H&E
Ki 67
CD117
Joensuu H et al. N Engl J Med. 2001;344:1...
Phase III Trial: US Intergroup S0033:Phase III Trial: US Intergroup S0033:
Time to Progression on CrossoverTime to Progres...
Time to Tumor ProgressionTime to Tumor Progression
Time (Months)
EstimatedTTPprobability(%)
Sunitinib (N=207)
Placebo (N=1...
%ofpatients
Months after randomization
1614121086420
100
80
60
40
20
0
Stop therapy (n=25)
Median PFS: 6 months
Continuous...
What dose ofWhat dose of
imatinib should Iimatinib should I
take?take?
EORTC Phase III Imatinib forEORTC Phase III Imatinib for
Advanced GISTAdvanced GIST
Progression-free Survival BenefitProgr...
Progression-free Survival ByProgression-free Survival By
Imatinib DoseImatinib Dose
Kit Exon 11 Mutation
Progression-free Survival ByProgression-free Survival By
Imatinib DoseImatinib Dose
Kit Exon 9 Mutation
Kit Mutation in GISTKit Mutation in GIST
Benefit from 800mg ImatinibBenefit from 800mg Imatinib
Odds RatioOdds Ratio P-val...
Tell me about theTell me about the
side effects…..side effects…..
Side effects: 400 vs. 800 mgSide effects: 400 vs. 800 mg
Toxic EventToxic Event AdjustedAdjusted pp-Value-Value
EdemaEdema...
Interruptions and ReductionsInterruptions and Reductions
of Therapyof Therapy
400 mg400 mg 800 mg800 mg
Treatment Interrup...
North American Intergroup Phase IIINorth American Intergroup Phase III
Study of ImatinibStudy of Imatinib
in Advanced GIST...
How do I know ifHow do I know if
imatinib is working?imatinib is working?
Confirmed Overall ResponsesConfirmed Overall Responses
with Gleevecwith Gleevec
Total
patients
N Confirmed partial
respons...
Best Response (B222)Best Response (B222)
400 mg400 mg
N=73N=73
n (%)n (%)
600 mg600 mg
N=74N=74
n (%)n (%)
All PatientsAll...
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0 0.5 1 1.5 2
Years
CI
400 mg 800 mg
Time to PR by RECISTTime to PR by RECIST
6 Mo...
J un 27, 2000 Oct 4, 2000
CT Scan Results
Bef or e I mat i ni b Af t er I mat i ni b
Background (cont)
Decrease in GIST intravenous contrast uptake after patient is treated for 8
weeks with imatinib mesylate
Overall Survival by Best ResponseOverall Survival by Best Response
(B222, Kaplan Meier Estimate)(B222, Kaplan Meier Estima...
10/8
Effects of Imatinib on GIST:Effects of Imatinib on GIST:
CT and PET findingsCT and PET findings
1/18
3/23
1/26
3/22
Pseudoprogression Early DuringPseudoprogression Early During
Treatment With Imatinib MesylateTreatment With Imatinib Mesyl...
1/12 3/30 5/24
Effects of Imatinib on GIST:Effects of Imatinib on GIST:
CT findingsCT findings
Modified RECIST for GISTModified RECIST for GIST
CT Size + Density (Choi)CT Size + Density (Choi)
 Tumor sizeTumor size d...
What is “genotyping?”What is “genotyping?”
Extracellular Domain (exon 9, 10.2%)
Juxtamembrane Domain (exon 11, 66.1%)
Tyrosine Kinase Domain I (exon 13/14, 1.2%)
Tyr...
Kit Mutation in GISTKit Mutation in GIST
Response to Imatinib (n=332)Response to Imatinib (n=332)
0%
10%
20%
30%
40%
50%
6...
Overall Survival by GenotypeOverall Survival by Genotype
(B222, Kaplan Meier Estimate)(B222, Kaplan Meier Estimate)
0 250 ...
Kit-Negative GISTKit-Negative GIST
IHC ResultIHC Result
PFSPFS
(2 year)(2 year)
OSOS
(2 year)(2 year)
Kit-negative GISTKit...
How will you know whetherHow will you know whether
my GIST comes back?my GIST comes back?
Type of ProgressionType of Progression
Stable
disease
Limited
progression
Widespread
progression
Stable
lesion
Progressing...
LimitedLimited
ProgressionProgression
Resistance to Imatinib Mesylate:Resistance to Imatinib Mesylate:
Recognition of Clonal EvolutionRecognition of Clonal Evol...
Secondary MutationSecondary Mutation
Heinrich et al, JCO 2006
What do I do if myWhat do I do if my
GIST is resistant toGIST is resistant to
imatinib?imatinib?
Therapy by Type ofTherapy by Type of
ProgressionProgression
 Limited or Nodular ProgressionLimited or Nodular Progression...
Hepatic Artery EmbolizationHepatic Artery Embolization
urtesy of Dr. R. DeMatteo.
Pre-
embolization
Post-
embolization
Metastatic GIST TrialsMetastatic GIST Trials
 Phase II studiesPhase II studies in advanced GISTin advanced GIST
 AMN107A...
SU11248 in Advanced GISTSU11248 in Advanced GIST
Sunitinib Malate, SutentSunitinib Malate, Sutent
R
A
N
D
O
M
I
Z
E
PD on
...
SU11248 in Advanced GISTSU11248 in Advanced GIST
Objective Response RatesObjective Response Rates
SunitinibSunitinib Place...
Time to Tumor ProgressionTime to Tumor Progression
Time (Months)
EstimatedTTPprobability(%)
Sunitinib (N=207)
Placebo (N=1...
Should I take imatinib after myShould I take imatinib after my
GIST was removed?GIST was removed?
Survival of GIST PatientsSurvival of GIST Patients
by Primary Tumor Sizeby Primary Tumor Size
DeMatteo et al, 2000
Post-operative Imatinib TrialsPost-operative Imatinib Trials
 Z9000:Z9000: ACOSOG Study of Adjuvant Imatinib inACOSOG Stu...
Preoperative Imatinib TrialsPreoperative Imatinib Trials
 MDACC ID03-0023MDACC ID03-0023: Preop/Postop Imatinib in: Preop...
Patient CharacteristicsPatient Characteristics
n=13n=13
CharacteristicCharacteristic ValueValue
Age (median)Age (median) 5...
Preoperative Imatinib ToxicityPreoperative Imatinib Toxicity
Grade 3/4Grade 3/4
ToxicityToxicity Number of PatientsNumber ...
PET Response at Day 5PET Response at Day 5
Pre-imatinib Post-imatinib (Day 5)
PET Response DataPET Response Data
n=12n=12
3 Days3 Days 5 Days5 Days 7 Days7 Days TotalTotal
RespondersResponders 33 22 3...
5 days5 days
post-imatinibpost-imatinib
Apoptosis After ImatinibApoptosis After Imatinib
Pre-Imatinib Post-Imatinib (3 days of therapy)
Effect of Imatinib on Apoptosis
Immunofluorescent TUNEL Assay
Will my kids getWill my kids get
GIST?GIST?
Familial GISTFamilial GIST
I
II
III
IV
III
I II
I
III IV V
III
VI
II
VII VIII
III IV
Jon Trent, MD, PhD
jtrent@mdanderson.org
Dept. of Sarcoma Medical Oncology
The University of Texas,
M. D. Anderson Cancer ...
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  • GIST represent a subset of sarcomas (tumors of mesenchymal origin) that develops in the gastrointestinal (GI) tract and may spread within the abdomen.
    GIST are relatively rare neoplasms, representing less than 1% of all tumors of the GI tract; nonetheless, GIST are the most common mesenchymal malignancy of the GI tract.
    The peak incidence seems to occur between 40 and 60 years of age.
    Men and women are affected equally, and it is unusual to find GIST in patients youngerthan 40.
    Approximately 4500 to 6000 cases of GIST occur annually in the United States. The prevalence of GIST is higher than its incidence, because the clinical course of the disease can last for 10 to 15 years.
    The definition of GIST is evolving and recently has been identified as a distinct clinical and histopathologic entity. In the past, GIST often were underdiagnosed because of confusion over classification and similarities to other tumor types.
  • It is now believed that GIST arise from mesenchymal precursor cells with the ability to differentiate into either smooth muscle or enteric neural cells, because GIST with smooth muscle or neural differentiation can each express KIT.
    This has led to speculation that GIST arise from cells of the enteric neural plexus, which also give rise to normal interstitial cells of Cajal (ICC). Because a subset of GIST expresses a neural phenotype, GIST now include the group of tumors previously known as GI pacemaker tumors (GIPacTs) or GI autonomic nerve tumors (GANTs).
    ICC are GI pacemaker cells that regulate gut peristalsis. They are important for the autonomous movement of the GI tract and require normal KIT function for their maturation, development, and survival. They develop from the gut mesenchyme, are not neural crest-derived cells, and do not express neural crest immunohistochemical markers such asS-100. ICC are uniformly KIT-positive.
  • <number>
    CGP 57148 and its B salt are potent and selective inhibitors of the Bcr-Abl, v-ABL and platelet-derived growth factor (PDGF) receptor tyrosine kinases in vitro and in cells. Submicromolar concentrations of the compound selectively inhibited Abl (v-Abl and Bcr-Abl kinases) autophosphorylation and PDGF-induced receptor autophosphorylation and cellular tyrosine phosphorylation. In contrast, ligand-induced growth factor receptor autophosphorylation in response to epidermal growth factor (EGF), insulin-like growth factor-I (IGF-I), insulin and stem cell factor (KIT ligand) showed no or weak inhibition by high concentrations of CGP 57148. Furthermore, autophosphorylation of the JAK-2 kinase, which is known to be activated by interleukin-3 (IL-3) signal transduction, and FMS and SRC autophosphorylation were not affected by the compound. CGP 57148B showed potent inhibition of PDGF-induced c-fos mRNA expression, whereas c-fos mRNA expression induced by EGF, fibroblast growth factor (FGF) or phorbol ester was insensitive to inhibition by the compound.
    In antiproliferative assays, the compound was more than 30-fold more potent in inhibiting PDGF-mediated growth of v-sis transformed BALB/c 3T3 cells (IC50 = 0.3 M) relative to inhibition of EGF-dependent BALB/MK cells, IL-3-dependent FDC-P1 cells and the T24 bladder carcinoma line. CGP 57148B was tested for antiproliferative activity on Bcr-Abl expressing 32D and MO7e cells and their IL-3-dependent parental cells. CGP 57148B had no effect on the proliferation of parental or v-src transformed cells at concentration up to 10 M. In contrast, 1 M CGP 57148 selectively killed Bcr-Abl expressing cells.
    CGP 57148B was tested for selective inhibition of CML colony formation using ex vivo human patient samples. The compound did not inhibit colony formation of normal bone marrow at 1 M. In contrast, when peripheral blood or bone marrow was obtained from CML patients a 60-90% inhibition of colony formation was seen with 1 M CGP 57148B. When colonies were assayed for the presence of Bcr-abl transcripts by PCR, less than 20% of the colonies that formed in the presence of 1 M CGP 57148B contained Bcr-abl transcripts. Combining this data with the 60-90% inhibition of colony formation, there was an overall decrease of Bcr-abl positive colonies of 92-98%.
    When tested in vivo using Bcr-abl, v-abl and v-sis transformed cells, CGP 57148B showed antitumor activity at tolerated doses. Antitumor activity was also shown against the U-373 MG and U-87 MG human astrocytomas which express PDGF and PDGF receptors. In contrast, CGP 57148B had no antitumor activity when tested using v-src transformed cells. Antitumor activity against v-abl tumors was highest when compound was administered by the i.v. or i.p. routes.
  • <number>
  • Patients with unresectable or metastatic GIST (N=129) received imatinib mesylate400 mg/d for 12 months in the BFR14 trial. These patients were then randomized to either continue therapy or to stop therapy. During the first 3 months following randomization, patients were given CT scans every month for 3 months, and then every 3 months until progression. Following progression, imatinib mesylate therapy would be reinitiated.
    Patients on the stop therapy arm of the trial had a median PFS of 6 months following randomization, while no patients on the continue therapy arm progressed after 7 months (P=0.0001). PFS on the stop therapy arm was comparable between patients who had initially achieved a CR or PR.
    Following imatinib mesylate reinitiation, most patients were able to reestablish tumor control, although 1 patient who had stopped therapy has died of disease.
    This trial demonstrates that imatinib mesylate therapy should be continued indefinitely, even following CR.
    Randomization for this trial has been suspended, and all patients are eligible forimatinib therapy.
  • <number>
  • <number>
  • <number>
  • <number>
    Pseudoprogression is uncommon, but can occur early in treatment.
    These images are from a 51-year-old male patient with primary GIST originating in the colon with peritoneal metastases. Although the patient appears to be progressing by anatomic criteria, 18FDG uptake was reduced by PET, and the tumor has undergone a decrease in density by CT, from 42 Hounsfield units (HU) to 30 HU.
  • _ Intratumoral hemorrage following treatment.
    _ max SUV vs. average HU for tumor density
    ODS, using tumor density, vessels, and size of solid tumor nodules in addition to the size of tumor, improved ----
  • <number>
  • <number>
  • <number>
    Clonal evolution of resistance may first appear as regions of a responding tumor with increased density.
    In a recent study (N=89), 26% of progressing patients developed a novel progressing nodule within an existing lesion. These new nodules were the first sign of progression in 78% of these patients.
    Over time, these foci may form a progressing nodule with different radiodensity from the progenitor lesion.
  • Hepatic artery embolization is an alternative palliative therapy for patients with tumors that cannot be resected.
    Embolization is performed by reducing the blood flow through the hepatic artery, which minimally affects healthy liver cells as they get their blood supply from the portal vein.
    Embolization may not be suitable for patients with liver diseases such as hepatitisor cirrhosis.
  • <number>
  • Tumors were stained for CD31 (red) and TUNEL (green) and quantifed by LSC.
  • Medical Update

    1. 1. Jon Trent, MD, PhD Assistant Professor Dept. of Sarcoma Medical Oncology The University of Texas, M. D. Anderson Cancer Center jtrent@mdanderson.org Gastrointestinal Stromal TumorGastrointestinal Stromal Tumor Life Fest 2006Life Fest 2006 www.ctos.org
    2. 2. BackgroundBackground
    3. 3. GIST OverviewGIST Overview  Most common GI sarcomaMost common GI sarcoma  0.2% of all GI tumors, but 80% of GI sarcomas0.2% of all GI tumors, but 80% of GI sarcomas  Distinct clinical and histopathologic entityDistinct clinical and histopathologic entity  Highest incidence in the 40-60 year age groupHighest incidence in the 40-60 year age group  Similar male/female incidenceSimilar male/female incidence  Many misclassified as leiomyosarcomaMany misclassified as leiomyosarcoma  GIST have an incidence of 14.5 per million annually and aGIST have an incidence of 14.5 per million annually and a prevalence of 129 per millionprevalence of 129 per million  Clinical presentation is variableClinical presentation is variable  pain, hemorrhage, anemia, anorexia, nausea, perforationpain, hemorrhage, anemia, anorexia, nausea, perforation
    4. 4. Median Overall Survival in Metastatic GISTMedian Overall Survival in Metastatic GIST
    5. 5. Chemotherapy TrialsChemotherapy Trials Advanced GISTAdvanced 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/GM–CSF 21 1 (5%) Temozolamide 19 0 (0%) TOTAL 280 19 (6.8%)
    6. 6. GIST OverviewGIST Overview  GIST share several characteristics with ICCGIST share several characteristics with ICC  Neuromuscular pacemaker cell of the GINeuromuscular pacemaker cell of the GI tracttract  Found in myenteric plexus throughoutFound in myenteric plexus throughout GI tractGI tract  Expression of CD34 in ~80% of casesExpression of CD34 in ~80% of cases  Expression of KIT (CD117) in ~95% ofExpression of KIT (CD117) in ~95% of casescases ICC = interstitial cells of Cajal. Corless et al. J Clin Oncol. 2004;22:3813. Sircar et al. Am J Surg Pathol. 1999;23:377.
    7. 7. Extracellular Domain (exon 9, 10.2%) Juxtamembrane Domain (exon 11, 66.1%) Tyrosine Kinase Domain I (exon 13/14, 1.2%) Tyrosine Kinase Domain II (exon 17, 0.6%) = common mutation site ATP Kit Receptor Structure
    8. 8. ATP Proliferation Survival Adhesion Invasion Metastasis Angiogenesis ADP + P Kit Receptor Phenotype
    9. 9. Formula: C30H35N7SO4 MW: 589.7 IImatinib Mesylatematinib Mesylate CH3SO3H N N N NH NH O N N  Rational drug designRational drug design  2-phenylamino pyrimidine2-phenylamino pyrimidine  Based on structure of ATPBased on structure of ATP binding sitebinding site  Highly water solubleHighly water soluble  Oral bioavailabilityOral bioavailability Inhibitor of selective tyrosine kinases bcr-abl PDGF-R c-kit Potent (IC50 ≈ 0.1µM)
    10. 10. ATP = imanitib contact point Proliferation Survival Adhesion Invasion Metastasis Angiogenesis Im atinib Kit Receptor Phenotype
    11. 11. Joensuu H et al. N Engl J Med. 2001;344:1052-1056. Marked Biologic Response Revealed by PET Scan Multiple liver and upper abdominal 18FDG-accumulating metastases A marked decrease in 18FDG uptake 4 weeks after starting imatinib mesylate
    12. 12. Pr et r eat ment One mont h of t her apy H&E ( at di agnos i s ) H&E Ki 67 CD117 Joensuu H et al. N Engl J Med. 2001;344:1052-1056. The First GIST Patient: Histology
    13. 13. What is the chance of imatinibWhat is the chance of imatinib helping me?helping me?
    14. 14. Clinical Trials ofClinical Trials of Imatinib in GISTImatinib 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 746746 -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.
    15. 15. 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
    16. 16. Low Dose Imatinib 400 mg/d High Dose Imatinib Progression Progression Off Protocol Treatment C R O S S O V E R High Dose Imatinib 800 mg/d Progression Off Protocol Treatment R A N D O M I Z A T I O N North American Sarcoma Intergroup Schema
    17. 17. Verweij, et al 2004 EORTC Phase III Imatinib forEORTC Phase III Imatinib for Advanced GISTAdvanced GIST Survival BenefitSurvival Benefit
    18. 18. How long do I takeHow long do I take imatinib?imatinib?
    19. 19. Pr et r eat ment One mont h of t her apy H&E ( at di agnos i s ) H&E Ki 67 CD117 Joensuu H et al. N Engl J Med. 2001;344:1052-1056. The First GIST Patient: Histology
    20. 20. Phase III Trial: US Intergroup S0033:Phase III Trial: US Intergroup S0033: Time to Progression on CrossoverTime to Progression on Crossover
    21. 21. Time to Tumor ProgressionTime to Tumor Progression Time (Months) EstimatedTTPprobability(%) Sunitinib (N=207) Placebo (N=105) Median (95% CI) 6.3 (3.7, 7.6) 1.5 (1.0, 2.3) Hazard ratio = 0.335 P<0.00001 100 90 80 70 60 50 40 30 20 10 0 0 3 6 9 12
    22. 22. %ofpatients Months after randomization 1614121086420 100 80 60 40 20 0 Stop therapy (n=25) Median PFS: 6 months Continuous therapy (n=23) P=0.0001 Discontinuation of Imatinib IncreasesDiscontinuation of Imatinib Increases the Risk of Progression (BFR14)the Risk of Progression (BFR14)  Patients who achieved clinical benefit after 12 months were randomizedPatients who achieved clinical benefit after 12 months were randomized to continue or to stop imatinib mesylate therapyto continue or to stop imatinib mesylate therapy  Randomization has been suspendedRandomization has been suspended Blay et al. Proc Am Soc Clin Oncol. 2004;23:815. Abstract 9006.
    23. 23. What dose ofWhat dose of imatinib should Iimatinib should I take?take?
    24. 24. EORTC Phase III Imatinib forEORTC Phase III Imatinib for Advanced GISTAdvanced GIST Progression-free Survival BenefitProgression-free Survival Benefit Verweij, et al 2004
    25. 25. Progression-free Survival ByProgression-free Survival By Imatinib DoseImatinib Dose Kit Exon 11 Mutation
    26. 26. Progression-free Survival ByProgression-free Survival By Imatinib DoseImatinib Dose Kit Exon 9 Mutation
    27. 27. Kit Mutation in GISTKit Mutation in GIST Benefit from 800mg ImatinibBenefit from 800mg Imatinib Odds RatioOdds Ratio P-valueP-value Exon 11Exon 11 (n=211)(n=211) 1.01.0 0.960.96 Exon 9Exon 9 (n=25)(n=25) 8.08.0 0.030.03 Wild-typeWild-type (n=33)(n=33) 1.51.5 0.620.62 Heinrich et al, ASCO 2050
    28. 28. Tell me about theTell me about the side effects…..side effects…..
    29. 29. Side effects: 400 vs. 800 mgSide effects: 400 vs. 800 mg Toxic EventToxic Event AdjustedAdjusted pp-Value-Value EdemaEdema <0.001<0.001 AnemiaAnemia <0.001<0.001 RashRash <0.001<0.001 FatigueFatigue <0.001<0.001 NauseaNausea <0.001<0.001 HemorrhageHemorrhage <0.001<0.001 DiarrheaDiarrhea 0.00260.0026 DyspneaDyspnea 0.0360.036 Pleuritic PainPleuritic Pain 0.0530.053 Verweij et al, 2004
    30. 30. Interruptions and ReductionsInterruptions and Reductions of Therapyof Therapy 400 mg400 mg 800 mg800 mg Treatment InterruptionTreatment Interruption 40%40% 64%64% -Hematologic-Hematologic 6%6% 7%7% -Non-Heme-Non-Heme 23%23% 43%43% Dose ReductionDose Reduction 16%16% 60%60% -Hematologic-Hematologic 2%2% 4%4% -Non-heme-Non-heme 10%10% 42%42%
    31. 31. North American Intergroup Phase IIINorth American Intergroup Phase III Study of ImatinibStudy of Imatinib in Advanced GISTin Advanced GIST DoseDose ReductionReduction 400 mg400 mg (376 pts)(376 pts) 800 mg800 mg (370 pts)(370 pts) 800 mg800 mg X-OverX-Over 11 10%10% 44%44% 16%16% 22 7%7% 26%26% 5%5% 33 2%2% 11%11% 0%0% 44 1%1% 4%4% 0%0% Dileo et al, ASCO 2005
    32. 32. How do I know ifHow do I know if imatinib is working?imatinib is working?
    33. 33. Confirmed Overall ResponsesConfirmed Overall Responses with Gleevecwith Gleevec Total patients N Confirmed partial response (%) 95% Confidence Interval 400mg 73 33 22-45 600mg 74 43 32-55 Total 147 38 30-46
    34. 34. Best Response (B222)Best Response (B222) 400 mg400 mg N=73N=73 n (%)n (%) 600 mg600 mg N=74N=74 n (%)n (%) All PatientsAll Patients N=147N=147 n (%)n (%) Complete ResponseComplete Response 00 2 (2.7)2 (2.7) 2 (1.4)2 (1.4) Partial ResponsePartial Response 50 (68.5)50 (68.5) 48(64.9)48(64.9) 98 (66.7)98 (66.7) Stable DiseaseStable Disease 10 (13.7)10 (13.7) 13 (17.6)13 (17.6) 23 (15.6)23 (15.6) ProgressionProgression 11 (15.1)11 (15.1) 6 (8.1)6 (8.1) 17 (11.6)17 (11.6) Not evaluableNot evaluable 2 (2.7)2 (2.7) 5 (6.8)5 (6.8) 7 (4.8)7 (4.8)
    35. 35. 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 0 0.5 1 1.5 2 Years CI 400 mg 800 mg Time to PR by RECISTTime to PR by RECIST 6 Months 3 Months 2 Months Cumulative incidence of CT responsesCumulative incidence of CT responses Verweij et al, ASCO 2003
    36. 36. J un 27, 2000 Oct 4, 2000 CT Scan Results Bef or e I mat i ni b Af t er I mat i ni b
    37. 37. Background (cont) Decrease in GIST intravenous contrast uptake after patient is treated for 8 weeks with imatinib mesylate
    38. 38. Overall Survival by Best ResponseOverall Survival by Best Response (B222, Kaplan Meier Estimate)(B222, Kaplan Meier Estimate) Number at Risk 0 2 40 2 80 2 Wks:Best Response CR Median Duration N/A 95% CI LL UL 172 N/A Number at Risk 0 98 40 97 80 92 Wks:Best Response PR Median Duration 248 Wks 95% CI LL UL 226 N/A Number at Risk 0 23 40 22 80 20 Wks:Best Response SD Median Duration N/A 95% CI LL UL 149 N/A Number at Risk 0 17 40 7 80 4 Wks:Best Response PD Median Duration 36 Wks 95% CI LL UL 15 56 Number at Risk 0 7 40 5 80 4 Wks:Best Response UNK Median Duration 144 Wks 95% CI LL UL 18 223 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Weeks Post First Dose 0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 216 228 240 252 264 SD (n=23): Median n/a PD (n=17): Median 36 wks PR (n=98): Median 248 wks [CR (n=2; median OS n/a) and unknown/NE (n=7; median OS 144 wks) not included]
    39. 39. 10/8 Effects of Imatinib on GIST:Effects of Imatinib on GIST: CT and PET findingsCT and PET findings 1/18 3/23 1/26 3/22
    40. 40. Pseudoprogression Early DuringPseudoprogression Early During Treatment With Imatinib MesylateTreatment With Imatinib Mesylate Choi et al. AJR Am J Roentgenol. 2004;183:1619. Pre-imatinib mesylate 2 months imatinib mesylate CT 18 FDG-PET
    41. 41. 1/12 3/30 5/24 Effects of Imatinib on GIST:Effects of Imatinib on GIST: CT findingsCT findings
    42. 42. Modified RECIST for GISTModified RECIST for GIST CT Size + Density (Choi)CT Size + Density (Choi)  Tumor sizeTumor size decrease ofdecrease of >>10%10% oror tumortumor density decrease ofdensity decrease of >>15%15% werewere highlyhighly correlatedcorrelated with decrease in SUV by >70% to awith decrease in SUV by >70% to a value <2.5 on PET.value <2.5 on PET.  RECIST criteriaRECIST criteria substantially underestimatesubstantially underestimate,, at least initially, the value of therapy withat least initially, the value of therapy with imatinib for GIST.imatinib for GIST.
    43. 43. What is “genotyping?”What is “genotyping?”
    44. 44. Extracellular Domain (exon 9, 10.2%) Juxtamembrane Domain (exon 11, 66.1%) Tyrosine Kinase Domain I (exon 13/14, 1.2%) Tyrosine Kinase Domain II (exon 17, 0.6%) = common mutation site ATP Kit Receptor Structure
    45. 45. Kit Mutation in GISTKit Mutation in GIST Response to Imatinib (n=332)Response to Imatinib (n=332) 0% 10% 20% 30% 40% 50% 60% 70% Exon 11 Exon 9 Wild-type Kit Mutation Site ObjectiveResponseRate
    46. 46. Overall Survival by GenotypeOverall Survival by Genotype (B222, Kaplan Meier Estimate)(B222, Kaplan Meier Estimate) 0 250 500 750 1000 1250 1500 0 10 20 30 40 50 60 70 80 90 100 Exon 9 23 22 18 14 11 11 No Mutation 9 5 3 3 3 3 Exon 11 86 82 81 73 64 53 P-value = 0.0012 Survival Number at Risk Days 0 250 500 750 1000 1250 Days OverallSurvival(%) Exon 11 Exon 9 No Mutation Median SurvivalMedian Survival Exon 11Exon 11 Not reachedNot reached Exon 9Exon 9 1347 days1347 days (192 wks)(192 wks) No mutNo mut 250 days250 days (36 wks)(36 wks)
    47. 47. Kit-Negative GISTKit-Negative GIST IHC ResultIHC Result PFSPFS (2 year)(2 year) OSOS (2 year)(2 year) Kit-negative GISTKit-negative GIST 43%43% 57%57% Kit-expressing GISTKit-expressing GIST 49%49% 77%77% P-valueP-value NSNS 0.010.01 Blackstein et al, ASCO 2005
    48. 48. How will you know whetherHow will you know whether my GIST comes back?my GIST comes back?
    49. 49. Type of ProgressionType of Progression Stable disease Limited progression Widespread progression Stable lesion Progressing lesion Nodular progression
    50. 50. LimitedLimited ProgressionProgression
    51. 51. Resistance to Imatinib Mesylate:Resistance to Imatinib Mesylate: Recognition of Clonal EvolutionRecognition of Clonal Evolution Courtesy of Dr. G.D. Demetri.
    52. 52. Secondary MutationSecondary Mutation Heinrich et al, JCO 2006
    53. 53. What do I do if myWhat do I do if my GIST is resistant toGIST is resistant to imatinib?imatinib?
    54. 54. Therapy by Type ofTherapy by Type of ProgressionProgression  Limited or Nodular ProgressionLimited or Nodular Progression  Hepatic Artery EmbolizationHepatic Artery Embolization  Hepatic Radio-frequency Catheter AblationHepatic Radio-frequency Catheter Ablation  Surgical ResectionSurgical Resection  Widespread progressionWidespread progression  Increase Imatinib to 800 mg dailyIncrease Imatinib to 800 mg daily  SunitinibSunitinib  Clinical TrialClinical Trial
    55. 55. Hepatic Artery EmbolizationHepatic Artery Embolization urtesy of Dr. R. DeMatteo. Pre- embolization Post- embolization
    56. 56. Metastatic GIST TrialsMetastatic GIST Trials  Phase II studiesPhase II studies in advanced GISTin advanced GIST  AMN107AMN107: Kit and Abl inhibitor: Kit and Abl inhibitor  AMG 706AMG 706:: High affinity Kit inhibitor and VEGFR inhibitorHigh affinity Kit inhibitor and VEGFR inhibitor  DasatinibDasatinib: High affinity Kit, Abl and Src inhibitor (+other: High affinity Kit, Abl and Src inhibitor (+other targets)targets)  SorafinibSorafinib: High affinity Kit inhibitor: High affinity Kit inhibitor  PerifosinePerifosine (AKT/MapK/p21 inhibitor)+(AKT/MapK/p21 inhibitor)+ImatinibImatinib: inhibit PI3K: inhibit PI3K activation of AKTactivation of AKT  G3139G3139 (antisense bcl-2) +(antisense bcl-2) + ImatinibImatinib : restore apoptosis: restore apoptosis  RAD0001RAD0001 (mTOR inhibitor)+Imatinib(mTOR inhibitor)+Imatinib  Phase I studiesPhase I studies in GISTs and other solid tumorsin GISTs and other solid tumors  IGF-1R inhibitorIGF-1R inhibitor  TRAILTRAIL
    57. 57. SU11248 in Advanced GISTSU11248 in Advanced GIST Sunitinib Malate, SutentSunitinib Malate, Sutent R A N D O M I Z E PD on imatinib Stop imatinib 4 weeks SU11248 (207) Placebo (105) PD PD Off 6 weeks
    58. 58. SU11248 in Advanced GISTSU11248 in Advanced GIST Objective Response RatesObjective Response Rates SunitinibSunitinib PlaceboPlacebo ImatinibImatinib 800mg*800mg* PRPR 7%7% 0%0% 6%6% SDSD 58%58% 50%50% 32%32% SD> 6 moSD> 6 mo 19%19% 0%0% NDND PDPD 20%20% 39%39% 48%48% NENE 14%14% 11%11% 13%13% *Escalation of imatinib from 400 mg to 800 mg daily.
    59. 59. Time to Tumor ProgressionTime to Tumor Progression Time (Months) EstimatedTTPprobability(%) Sunitinib (N=207) Placebo (N=105) Median (95% CI) 6.3 (3.7, 7.6) 1.5 (1.0, 2.3) Hazard ratio = 0.335 P<0.00001 100 90 80 70 60 50 40 30 20 10 0 0 3 6 9 12
    60. 60. Should I take imatinib after myShould I take imatinib after my GIST was removed?GIST was removed?
    61. 61. Survival of GIST PatientsSurvival of GIST Patients by Primary Tumor Sizeby Primary Tumor Size DeMatteo et al, 2000
    62. 62. Post-operative Imatinib TrialsPost-operative Imatinib Trials  Z9000:Z9000: ACOSOG Study of Adjuvant Imatinib inACOSOG Study of Adjuvant Imatinib in GISTGIST  Z9001Z9001: ACOSOG: ACOSOG RandomizedRandomized Study of AdjuvantStudy of Adjuvant Imatinib Versus Placebo in GISTImatinib Versus Placebo in GIST  Primary Objective is survivalPrimary Objective is survival  Secondary objective to obtain tumor before ImatinibSecondary objective to obtain tumor before Imatinib and at recurrenceand at recurrence  Resected < 10 weeks prior to ImatinibResected < 10 weeks prior to Imatinib  High risk for local or distant failure (High risk for local or distant failure (>> 3 cm primary,3 cm primary, intraperitoneal hemorrhage, tumor rupture)intraperitoneal hemorrhage, tumor rupture)  Z9002Z9002: Adjuvant Duration?: Adjuvant Duration?
    63. 63. Preoperative Imatinib TrialsPreoperative Imatinib Trials  MDACC ID03-0023MDACC ID03-0023: Preop/Postop Imatinib in: Preop/Postop Imatinib in Patients with Resectable GISTPatients with Resectable GIST  Laboratory correlationsLaboratory correlations  Clinical endpoints of DFS, OSClinical endpoints of DFS, OS  RTOG S-0132RTOG S-0132: Preoperative Imatinib in Patients: Preoperative Imatinib in Patients with Potentially Resectable GISTwith Potentially Resectable GIST  Laboratory correlationsLaboratory correlations  Clinical endpoints of DFS, OSClinical endpoints of DFS, OS  Imatinib to maximum responseImatinib to maximum response
    64. 64. Patient CharacteristicsPatient Characteristics n=13n=13 CharacteristicCharacteristic ValueValue Age (median)Age (median) 52 (range 38-67)52 (range 38-67) Gender (M/F)Gender (M/F) 7/67/6 Primary Site of TumorPrimary Site of Tumor - Stomach- Stomach 66 - Small Intestine- Small Intestine 55 - Colon- Colon 22 Duration of ImatinibDuration of Imatinib - 3 days- 3 days 44 - 5 days- 5 days 55 - 7 days- 7 days 44
    65. 65. Preoperative Imatinib ToxicityPreoperative Imatinib Toxicity Grade 3/4Grade 3/4 ToxicityToxicity Number of PatientsNumber of Patients ((n=13n=13)) Nausea/emesisNausea/emesis 22 Abdominal painAbdominal pain 11 GI HemorrhageGI Hemorrhage 11 HypovolemiaHypovolemia 11 NoneNone 1111 Patients able to finish 1 year of therapy: 7/9 Patients with recurrence: 1
    66. 66. PET Response at Day 5PET Response at Day 5 Pre-imatinib Post-imatinib (Day 5)
    67. 67. PET Response DataPET Response Data n=12n=12 3 Days3 Days 5 Days5 Days 7 Days7 Days TotalTotal RespondersResponders 33 22 33 88 Non-responderNon-responder 11 22 11 44 Courtesy Homer Macapinlac, M. D. PET-CT imaging
    68. 68. 5 days5 days post-imatinibpost-imatinib Apoptosis After ImatinibApoptosis After Imatinib
    69. 69. Pre-Imatinib Post-Imatinib (3 days of therapy) Effect of Imatinib on Apoptosis Immunofluorescent TUNEL Assay
    70. 70. Will my kids getWill my kids get GIST?GIST?
    71. 71. Familial GISTFamilial GIST I II III IV III I II I III IV V III VI II VII VIII III IV
    72. 72. Jon Trent, MD, PhD jtrent@mdanderson.org Dept. of Sarcoma Medical Oncology The University of Texas, M. D. Anderson Cancer Center Gastrointestinal Stromal TumorsGastrointestinal Stromal Tumors A Paradigm of Targeted Anti-Tumor Therapy

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