medical update
TRANSCRIPT
Jon Trent, MD, PhD
Assistant ProfessorDept. of Sarcoma Medical OncologyThe University of Texas, M. D. Anderson Cancer Center
Gastrointestinal Stromal TumorGastrointestinal Stromal TumorLife Fest 2006Life Fest 2006
www.ctos.org
BackgroundBackground
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 GIST have an incidence of 14.5 per million annually and a prevalence of 129 per millionannually and a prevalence of 129 per million
Clinical presentation is variableClinical presentation is variable pain, hemorrhage, anemia, anorexia, nausea, pain, hemorrhage, anemia, anorexia, nausea,
perforationperforation
Median Overall Survival in Metastatic Median Overall Survival in Metastatic GISTGIST
Chemotherapy TrialsChemotherapy TrialsAdvanced 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%)
GIST OverviewGIST Overview
GIST share several characteristics GIST share several characteristics with ICCwith ICC Neuromuscular pacemaker cell of Neuromuscular pacemaker cell of
the GI tractthe GI tract Found in myenteric plexus Found in myenteric plexus
throughout GI tractthroughout GI tract Expression of CD34 in ~80% of Expression of CD34 in ~80% of
casescases Expression of KIT (CD117) in ~95% Expression of KIT (CD117) in ~95%
of casesof casesICC = interstitial cells of Cajal.Corless et al. J Clin Oncol. 2004;22:3813.Sircar et al. Am J Surg Pathol. 1999;23:377.
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
ATP
ProliferationSurvival
AdhesionInvasion
MetastasisAngiogenesis
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 drug design 2-phenylamino 2-phenylamino
pyrimidinepyrimidine Based on structure of Based on structure of
ATP binding siteATP binding site Highly water solubleHighly water soluble Oral bioavailabilityOral bioavailability
Inhibitor of selective tyrosine kinases
bcr-ablPDGF-Rc-kit
Potent (IC50
0.1M)
ATP
= imanitib contact point
ProliferationSurvival
AdhesionInvasion
MetastasisAngiogenesis
Imatinib
Kit Receptor Phenotype
Pretreatment
One month of therapy
H&E (at diagnosis)
H&E
Ki 67
CD117
Joensuu H et al. N Engl J Med. 2001;344:1052-1056.
The First GIST Patient: Histology
What is the chance of What is the chance of imatinib helping me?imatinib helping me?
Clinical Trials of Clinical 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.
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
Low DoseImatinib
400 mg/d
High DoseImatinibProgression Progression
Off ProtocolTreatment
CROSSOVER
High Dose Imatinib
800 mg/dProgression Off Protocol Treatment
RANDOMIZATION
North American Sarcoma IntergroupSchema
Verweij, et al 2004
EORTC Phase III EORTC Phase III Imatinib for Advanced Imatinib for Advanced
GISTGISTSurvival BenefitSurvival Benefit
How long do I How long do I take imatinib?take imatinib?
Pretreatment One month of therapy
H&E (at diagnosis)
H&E
Ki 67
CD117
Joensuu H et al. N Engl J Med. 2001;344:1052-1056.
The First GIST Patient: Histology
Phase III Trial: US Intergroup Phase III Trial: US Intergroup S0033: Time to Progression on S0033: Time to Progression on
CrossoverCrossover
Time to Tumor Time to Tumor ProgressionProgression
Time (Months)
Est
imat
ed T
TP
pro
bab
ilit
y (%
) Sunitinib (N=207)Placebo (N=105)
Median (95% CI)6.3 (3.7, 7.6)1.5 (1.0, 2.3)
Hazard ratio = 0.335P<0.00001
100
90
80
70
60
50
40
30
20
10
00 3 6 9 12
% o
f p
atie
nts
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 Discontinuation of Imatinib Increases the Risk of Increases the Risk of Progression (BFR14)Progression (BFR14)
Patients who achieved clinical benefit after 12 months were Patients who achieved clinical benefit after 12 months were randomized to continue or to stop imatinib mesylate therapyrandomized to continue or to stop imatinib mesylate therapy
Randomization has been suspended Randomization has been suspended
Blay et al. Proc Am Soc Clin Oncol. 2004;23:815. Abstract 9006.
What dose of What dose of imatinib should I imatinib should I
take?take?
EORTC Phase III EORTC Phase III Imatinib for Advanced Imatinib for Advanced
GISTGISTProgression-free Survival BenefitProgression-free Survival Benefit
Verweij, et al 2004
Progression-free Survival By Progression-free Survival By Imatinib DoseImatinib DoseKit Exon 11 Mutation
Progression-free Survival By Progression-free Survival By Imatinib DoseImatinib DoseKit Exon 9 Mutation
Kit Mutation in GISTKit Mutation in GISTBenefit from 800mg ImatinibBenefit from 800mg Imatinib
Odds RatioOdds Ratio P-valueP-valueExon 11Exon 11
(n=211)(n=211)1.01.0 0.960.96
Exon 9 Exon 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
Tell me about the Tell me about the side effects…..side effects…..
Side effects: 400 vs. 800 mgSide effects: 400 vs. 800 mg
Toxic EventToxic Event Adjusted Adjusted pp-Value-ValueEdemaEdema <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
Interruptions and Interruptions and Reductions of TherapyReductions of Therapy
400 400 mgmg
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%
North American Intergroup North American Intergroup Phase III Study of Imatinib Phase III Study of Imatinib
in Advanced GISTin Advanced GIST
Dose Dose 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
How do I know if How do I know if imatinib is imatinib is working?working?
Confirmed Overall Confirmed Overall Responses Responses
with Gleevecwith GleevecTotalpatients
N Confirmed partialresponse
(%)
95%Confidence
Interval400mg 73 33 22-45
600mg 74 43 32-55
Total 147 38 30-46
Best Response (B222)Best Response (B222)
400 mg 400 mg N=73N=73
n (%)n (%)
600 mg 600 mg N=74N=74
n (%)n (%)
All Patients All Patients N=147N=147
n (%)n (%)
Complete Complete ResponseResponse
00 2 (2.7)2 (2.7) 2 (1.4)2 (1.4)
Partial Partial ResponseResponse
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)
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
Jun 27, 2000 Oct 4, 2000
CT Scan Results
Before Imatinib After Imatinib
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 Estimate)
Number at Risk0
2
40
2
80
2
Wks:Best Response
CR
MedianDuration
N/A
95% CILL UL
172 N/A
Number at Risk0
98
40
97
80
92
Wks:Best Response
PR
MedianDuration
248 Wks
95% CILL UL
226 N/A
Number at Risk0
23
40
22
80
20
Wks:Best Response
SD
MedianDuration
N/A
95% CILL UL
149 N/A
Number at Risk0
17
40
7
80
4
Wks:Best Response
PD
MedianDuration
36 Wks
95% CILL UL
15 56
Number at Risk0
7
40
5
80
4
Wks:Best Response
UNK
MedianDuration
144 Wks
95% CILL UL
18 2230.0
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]
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 During Pseudoprogression Early During Treatment With Imatinib MesylateTreatment With Imatinib Mesylate
Choi et al. AJR Am J Roentgenol. 2004;183:1619.
Pre-imatinib mesylate 2 monthsimatinib mesylate
CT
18FDG-PET
1/12 3/30 5/24
Effects of Imatinib on GIST:Effects of Imatinib on GIST:CT findingsCT findings
Modified RECIST for Modified RECIST for GISTGIST
CT Size + Density (Choi)CT Size + Density (Choi) Tumor size Tumor size decrease of decrease of >>10%10% oror tumor tumor
density decrease of density decrease of >>15%15% were were highly highly correlatedcorrelated with decrease in SUV by with decrease in SUV by >70% to a value <2.5 on PET.>70% to a value <2.5 on PET.
RECIST criteria RECIST criteria substantially substantially underestimateunderestimate, at least initially, the , at least initially, the value of therapy with imatinib for GIST. value of therapy with imatinib for GIST.
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%)
Tyrosine Kinase Domain II (exon 17, 0.6%)
= common mutation site
ATP
Kit Receptor Structure
Kit Mutation in GISTKit Mutation in GISTResponse 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
Ob
jecti
ve R
esp
on
se R
ate
Overall Survival by GenotypeOverall Survival by Genotype(B222, Kaplan Meier Estimate)(B222, Kaplan Meier Estimate)
0 250 500 750 1000 1250 15000
10
20
30
40
50
60
70
80
90
100
Exon 9 23 22 18 14 11 11No 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
Ove
rall
Surv
ival
(%)
Exon 11
Exon 9
No Mutation
Median SurvivalMedian Survival
Exon 11Exon 11 Not Not reachedreached
Exon 9Exon 9 1347 days1347 days
(192 wks)(192 wks)
No mutNo mut 250 days250 days
(36 wks)(36 wks)
Kit-Negative GISTKit-Negative GIST
IHC ResultIHC ResultPFS PFS
(2 year)(2 year)OS OS
(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
How will you know How will you know whether my GIST comes whether my GIST comes
back?back?
Type of Progression Type of Progression
Stable
disease
Limited
progression
Widespread
progressionStable lesion
Progressing lesion
Nodular
progression
Limited Limited ProgressionProgression
Resistance to Imatinib Mesylate: Resistance to Imatinib Mesylate: Recognition of Clonal EvolutionRecognition of Clonal Evolution
Courtesy of Dr. G.D. Demetri.
Secondary MutationSecondary Mutation
Heinrich et al, JCO 2006
What do I do if What do I do if my GIST is my GIST is resistant to resistant to imatinib?imatinib?
Therapy by Type of Therapy by Type of ProgressionProgression
Limited or Nodular ProgressionLimited or Nodular Progression Hepatic Artery EmbolizationHepatic Artery Embolization Hepatic Radio-frequency Catheter Hepatic Radio-frequency Catheter
AblationAblation Surgical ResectionSurgical Resection
Widespread progressionWidespread progression Increase Imatinib to 800 mg dailyIncrease Imatinib to 800 mg daily SunitinibSunitinib Clinical TrialClinical Trial
Hepatic Artery EmbolizationHepatic Artery Embolization
Courtesy of Dr. R. DeMatteo.
Pre-embolization
Post-embolization
Metastatic GIST TrialsMetastatic GIST Trials Phase II studiesPhase II studies in advanced GIST in advanced GIST
AMN107AMN107: Kit and Abl inhibitor: Kit and Abl inhibitor AMG 706AMG 706:: High affinity Kit inhibitor and VEGFR High affinity Kit inhibitor and VEGFR
inhibitorinhibitor DasatinibDasatinib: High affinity Kit, Abl and Src inhibitor : High affinity Kit, Abl and Src inhibitor
(+other targets)(+other targets) SorafinibSorafinib: High affinity Kit inhibitor: High affinity Kit inhibitor
PerifosinePerifosine (AKT/MapK/p21 inhibitor)+ (AKT/MapK/p21 inhibitor)+ImatinibImatinib: inhibit : inhibit PI3K activation of AKTPI3K activation of AKT
G3139 G3139 (antisense bcl-2) +(antisense bcl-2) + Imatinib Imatinib : restore apoptosis: restore apoptosis RAD0001RAD0001 (mTOR inhibitor)+Imatinib (mTOR inhibitor)+Imatinib
Phase I studiesPhase I studies in GISTs and other solid tumors in GISTs and other solid tumors IGF-1R inhibitorIGF-1R inhibitor TRAILTRAIL
SU11248 in Advanced SU11248 in Advanced GISTGIST
Sunitinib Malate, SutentSunitinib Malate, Sutent
RANDOMIZE
PD on imatinib
Stop imatinib4 weeks
SU11248 (207)
Placebo (105) PD
PD
Off6 weeks
SU11248 in Advanced SU11248 in Advanced GISTGIST
Objective Response RatesObjective Response Rates
SunitinibSunitinib PlaceboPlacebo Imatinib Imatinib 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.
Time to Tumor Time to Tumor ProgressionProgression
Time (Months)
Est
imat
ed T
TP
pro
bab
ilit
y (%
) Sunitinib (N=207)Placebo (N=105)
Median (95% CI)6.3 (3.7, 7.6)1.5 (1.0, 2.3)
Hazard ratio = 0.335P<0.00001
100
90
80
70
60
50
40
30
20
10
00 3 6 9 12
Should I take imatinib Should I take imatinib after my GIST was after my GIST was
removed?removed?
Survival of GIST Patients Survival of GIST Patients by Primary Tumor Sizeby Primary Tumor Size
DeMatteo et al, 2000
Post-operative Imatinib Post-operative Imatinib TrialsTrials
Z9000: Z9000: ACOSOG Study of Adjuvant Imatinib ACOSOG Study of Adjuvant Imatinib in GISTin GIST
Z9001Z9001: ACOSOG : ACOSOG RandomizedRandomized Study of Study of Adjuvant Imatinib Versus Placebo in GIST Adjuvant Imatinib Versus Placebo in GIST
Primary Objective is survivalPrimary Objective is survival Secondary objective to obtain tumor before Secondary objective to obtain tumor before
Imatinib and at recurrenceImatinib and 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?
Preoperative Imatinib Preoperative Imatinib TrialsTrials
MDACC ID03-0023MDACC ID03-0023: Preop/Postop : Preop/Postop Imatinib in Patients with Resectable GISTImatinib in Patients with Resectable GIST Laboratory correlationsLaboratory correlations Clinical endpoints of DFS, OSClinical endpoints of DFS, OS
RTOG S-0132RTOG S-0132: Preoperative Imatinib in : Preoperative Imatinib in Patients with Potentially Resectable GISTPatients with Potentially Resectable GIST Laboratory correlationsLaboratory correlations Clinical endpoints of DFS, OSClinical endpoints of DFS, OS Imatinib to maximum responseImatinib to maximum response
Patient CharacteristicsPatient Characteristicsn=13n=13
CharacteristicCharacteristic ValueValueAge (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
Preoperative Imatinib ToxicityPreoperative Imatinib ToxicityGrade 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: 7/9Patients with recurrence: 1
PET Response at Day 5PET Response at Day 5
Pre-imatinib Post-imatinib (Day 5)
PET Response DataPET Response Datan=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
5 days 5 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 get Will 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
Dept. of Sarcoma Medical OncologyThe University of Texas, M. D. Anderson Cancer Center
Gastrointestinal Stromal TumorsGastrointestinal Stromal Tumors
A Paradigm of Targeted Anti-Tumor Therapy