gastrointestinal stromal tumor (gist,...
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Gastrointestinal Stromal Tumor(GIST, 위장관 기질 종양)
강윤구 / 류민희 / 류백렬
서울아산병원 종양내과서울아산병원 종양내과
What is GIST ?
• Formerly defined as sarcoma (smooth muscle Tm y (or neural Tm) ~ 1990s
• Paradigm for molecular targeted therapy in solid TmParadigm for molecular targeted therapy in solid Tm• The most common mesenchymal tumor of GI tract• Arising from interstitial cell of Cajal (pacemaker for• Arising from interstitial cell of Cajal (pacemaker for
peristaltic contraction)P th ti ll d i b ti ti t ti i• Pathogenetically driven by activation mutations in KIT or PDGFRA
Landmark Discoveries in GISTLandmark Discoveries in GIST
279:577-580, 1998
299:708-710, 2003
Landmark Trial in GISTLandmark Trial in GISTwith Glivec
Demetri et al. NEJM 2002
세포막의 KIT 및 PDGFRA 단백세포막의 KIT 및 PDGFRA 단백
− Extracellular domain (EC)−5개의 immunoglobulin− 정상 리간드 부착 부위
Transmembrane domain
Tyrosine kinase domain I (TKI)
Juxtamembrane domain (JM): Regulator
(ATP binding pocket)
Tyrosine kinase domain II (TKII)(Kinase activation loop)
Mechanisms of KIT Activation in GIST
RegulatorRegulator
Normal GIST Hirota et al. Science 1998Kitamura et al. Mutation Res 2001
KIT and PDGFRA Mutations in GISTKIT and PDGFRA Mutations in GIST
KIT PDGFRAKIT PDGFRA
Asan Medical Center
Total 87.4% 80.4%
Cell membraneExon 9 (11%) 6.2%
Cell membraneExon 12 (0.9%)Exon 14 (0.3%)
Exon 11 (67.5%)Exon 13 (0.9%)
70.6%0%
0%0%
Exon 18 (6.3%)
( )
Exon 17 (0.5%) 0.5% 3.1%
Heinrich et al. Hum Pathol 2002 Kim et al. Clin Cancer Res 2004
GIST: EpidemiologyGIST: Epidemiology• Incidence: 10 20 / million• Incidence: 10 – 20 / million• Median age: 55 – 65• Gender: M >/= F• Malignant: 20 – 30%Malignant: 20 30%• Sites
St h 60 70%– Stomach: 60 – 70%– Small intestine: 20 – 30%– Colon & rectum: 5%– Esophagus: < 5%– Omentum & mesentery: rare
Diagnosis of GISTDiagnosis of GIST
• Primary tumor in abdominal cavity: GI tract, peritoneump
Diagnosis of GISTDiagnosis of GIST
• Primary tumor in abdominal cavity: GI tract, peritoneump
• Characteristic histologic features
Spindle cell (70%) Mixed type (10%)Epithelioid cell (20%)
Diagnosis of GISTDiagnosis of GIST
• Primary tumor in abdominal cavity: GI tract, peritoneump
• Characteristic histologic features
• Immunohistochemistry– If CD117(+) in cytoplasm: diagnosis made
Diagnosis of GISTDiagnosis of GIST
• Primary tumor in abdominal cavity: GI tract, peritoneump
• Characteristic histologic features
• Immunohistochemistry– If CD117(-); 4-5%
: should be CD34(+), Desmin(-?), S100(-)• DNA seqencing of Kit exon 11, 9, 13, 17, and
PDGFRA exon 12, 18 – If mutation(+), diagnosis made
St i f GISTStaging of GIST
No specific staging system Localized ? Resectable ? Localized ?, Resectable ? Abdomen / pelvis dynamic CT scan
St i f GISTStaging of GIST
• Rare metastasis to extraabdominal organs• PET scan is rarely neededPET scan is rarely needed
Risk Stratification of GIST
Miettinen et al, Semin Diagn Pathol 2006
Conventional Tx of GIST• Surgery
– The only curative approach– Complete gross resection is essential, but wide resection
margin or routine lymphadenectomy is not necessary
• Radiation– Occasionally used for symptom palliation
• Chemotherapy– Doxorubicin - containing regimens– 5% response in GIST (ASCO 2000)
Targeted therapy for GISTTargeted therapy for GIST
I ti ib M l t Gli GlImatinib Mesylate: Glivec, GleevecSmall Molecule Tyrosine Kinase Inhibitory
C H N O•CH SOC29H31N7O•CH4SO3
MW 589.7
Class: Phenylaminopyrimidines
Druker et al. Nat Med 1996
KIT / PDGFRA 단백을 통한 세포 내 신호전달KIT / PDGFRA 단백을 통한 세포 내 신호전달
Substrate
Effector
TK domains
PP PADP P
PATP
Imatinib
PP PATP 신호전달
Savage and Antman. N Engl J Med 2002Scheijen and Griffin. Oncogene 2002
Imatinib: Target SelectivityImatinib: Target Selectivity
Kinase IC50 [
Abl 0 1 0 3
Kinase IC50 [
Flt 3 10v-Abl 0.1-0.3Bcr-Abl(p210) 0.25
Flt-3 >10c-Fms and v-Fms >10
Bcr-Abl(p185) 0.25TEL-Abl 0.35
EGF receptor >100c-erbB2 >100
c-Kit 0.1PDGF receptor 0.1
Insulin receptor >100IGF-I receptor >100
TEL-PDGF receptor 0.15 v-Src >10JAK-2 >100
Druker et al. Nat Med 1996
Imatinib for GIST: Pivotal Phase II Trial
Imatinib mesylate
(400 mg/d)
Metastatic or unresectable GIST (N=147)
PD Continue to treat as long
as benefit(N 147) as benefit
Imatinib mesylate (600 mg/d)
Demetri et al. NEJM 2002
Imatinib for GIST: Pivotal Phase II Trial
Demetri et al. NEJM 2002
Improved Survival with ImatinibImproved Survival with ImatinibCompared with Historical Conventional Chemotherapy Data
100
60
80
(%)
Imatinib (pooled 400 mg + 600 mg)
40
60
urvi
val (
20
Su
SWOG S8616/S9627
0 1 2 3 4 50
Years after registrationg
Blanke et al. 2004 ASCO GI Cancers Symposium
What is Optimal Dose ofWhat is Optimal Dose of Imatinib ?
Phase I Study of Imatinib- EORTC -- EORTC -
400 mg qd 300 mg bid 400 mg bid 500 mg bid(n=8) (n=8) (n=18) (n=8)(n=8) (n=8) (n=18) (n=8)
DLT Gr III Nausea (3)G III d (1)Gr III edema (1)Gr III dyspnea (1)
Mean DI 98% 89% 89% 80%
Lancet 2001:1421Eur J Cancer 2002:S83
Phase III Trials of 400 mg/d vs 800 mg/dg g: EORTC 62005 and US Intergroup S0033
Imatinib mesylate
(400 mg/d)
Metastatic or unresectable GIST
Followfor
PFS
PDPFS
Imatinib mesylate (800 mg/d)
Benjamin et al. Proc Am Soc Clin Oncol 2003. Abstract 3271Rankin et al. Proc Am Soc Clin Oncol 2004. Abstract 9005Verweij et al. Proc Am Soc Clin Oncol 2003. Abstract 3272
800 mg/d was NOT better than 400 mg/d g g
800 mg/d was NOT better than 400 mg/d g gEORTC 62005 US Intergroup S0033
PFS
OS
Verweij et al. Lancet 2004 Blanke et al. J Clin Oncol 2008
Pivotal Phase II Trial of Imatinib for GIST:Pivotal Phase II Trial of Imatinib for GIST: Long-Term Results
• 84% of patients showed a clinical benefit– 68% PR/CR
– 16% stable disease (SD)– 16% stable disease (SD)
• Time to Response: 0.8 – 39 mos (median 2.7 mos)
• Median duration of response: 29 mos
M di ll i l (OS) 57• Median overall survival (OS): 57 mos
• No difference between doses of 400 and 800 mg/d
Blanke et al. JCO 2008
g
Any difference of imatinib efficacy among the genotypes
f GIST ?of GIST ?
Response to Imatinib by Genotypep y yp(Pivotal phase II trial)
Blanke, et al. 2006 ASCO GI Cancer Symposium
Overall Survival by Genotype(Pivotal phase II trial)
Blanke, et al. 2006 ASCO GI Cancer Symposium
MetaGISTPrognostic value of Mutation StatusProgression-Free Survival Overall Survival
708090
100
708090
100
30405060
3040506070
0 1 2 3 4 50
1020
2 50 1 3 40
1020
KIT exon 11 mutants – KIT exon 9 mutants – Wild types - Other
Years Years
Median PFS (months) 26 / 13 / 16 / 11
3-year estimate (%) 38 / 11 / 27 / 9
Median OS (months) 60 / 31 / 43 / 34
3-year estimate (%) 69 / 44 / 57 / 46
Van Glabbeke # 10004
Continuous Development ofContinuous Development of Resistance after Imatinib Treatment
Imatinib 400 mgTwice daily
100y
Once daily80
PFS
(%) 60
40P 40
20
00 3 6 9 12 15 18 21 24 27 30
Verweij J et al. Lancet 2004
Time (months)
What can we doWhat can we do after failure of Imatinib ?after failure of Imatinib ?
T t t ft f il f i ti ibTreatment after failure of imatinib
Focal progression– Local ablation: Surgery, RFA, Chemoembolization
T t t ft f il f i ti ibTreatment after failure of imatinib
Focal progression– Local ablation: Surgery, RFA, Chemoemolization
General progression General progression
Mechanism of Resistance
Lack of Imatinib relative to KIT/PDGFRA Lack of Imatinib relative to KIT/PDGFRA
- KIT/PDGF 수용체의 과발현KIT/PDGF 수용체의 과발현
- 글리벡의 체내 분포의 변화
Acquisition of Resistant Mutation of Receptor
Activation of other pathways
T t t ft f il f i ti ibTreatment after failure of imatinib
Focal progression– Local ablation: Surgery, RFA, Chemoemolization
General progression General progression– Dose escalation
Imatinib Plasma Level Correlates with TTP after Treatment (Pivotal phase II trial)
Demetri et al. ASCO-GI 2008
MetaGISTPredictive value of Genotype: PFS
Median PFS (months) 6 / 19
KIT exon 9 mutants
80
90
100
Median PFS (months) 6 / 19
3-year estimate (%) 5 / 17
P value (logrank test) 0.01760
70
80
40
50
60
Kit exon 9 mutatnt800 mg
20
30
800 mg400 mg
0 1 2 3 4 50
10
0 1 2 3 4 5
Years
Van Glabbeke # 10004
T t t ft f il f i ti ibTreatment after failure of imatinib
Focal progression– Local ablation: Surgery, RFA, Chemoembolization
General progression General progression– Dose escalation– Other TKIs
Sunitinib
H3CO
N
CH3
CH3
NF
H3C
CH3
NH
N CH3
NH
OH
F
VEGFR-2VEGFR-1
VEGFR-3
PDGFR-α
CSF-1RPDGFR-β
VEGFR-3KITFLT3
Mendel et al. Clin Cancer Res 2003
Ph III T i l f S iti ibPhase III Trial of Sunitinib in Imatinib-resistant/-intolerant GIST
Conducted at 56 sites in Europe, USA, Australia and Asia (Singapore)
Sunitinib (n=243)Continue aslong as clinicalSunitinib
(S iti ib
50 mg/day, 4 weeks on, 2 weeks offImatinib-refractory or -intolerant GIST
Randomization2:1
long as clinical benefit
Sunitinib
(Sunitinib:placebo) Placebo (n=118)
-intolerant GISTpatients
PlaceboCross over tosunitinib atprogression
4 weeks on, 2 weeks offprogression
Demetri et al. Lancet 2006
Ti t P iTime to Progression
Demetri et al. Lancet 2006
Other TKIs in Clinical TrialsOther TKIs in Clinical TrialsDrug Targets Phase ResultsDrug Targets Phase Results
Nilotinib(AMN 107)
BCR-ABL, KIT, PDGFR
III(1st 2nd
1st and 2nd line trials on going 3rd line trial finished(AMN-107) PDGFR (1st, 2nd,
3rd line)going, 3 line trial finished
Masitinib KIT, PDGFR, Lyn III On going, , y g g
Vatalanib(PTK-787)
KIT, PDGFR, VEGFRs,
II 13% PR+53% SD in 15 imatinib-resist 1)
Sorafenib KIT, PDGFR, VEGFRs, RAF,
FLT3 RET
II 13% PR+ 58% SD in 24 imatinib/sunitinib-resist 2)
FLT3, RETDasatinib
(BMS-354825)Src/Abl, KIT,
PDGFRII
(1st line)On going
1) Joenssu et al. Ann Oncol 20072) Nimeiri et al. GI-ASCO 2008
( ) (1 line)
Future strategies after failure of imatinib
Combinations of TKIs targeting KIT / PDGFRA
Destruction or downregulation of KIT / PDGFRA
Inhibition of downstream targets of KIT / PDGFRAg
연구중인 약제들연구중인 약제들
Inhibit KIT production Destroy KIT
• Transcription inhibitorsFlavopiridol (CDK inhibitor):
• HSP90 inhibitorsKIT/PDGFRA is one of the– Flavopiridol (CDK inhibitor):
– phase I trial of flavopiridol + doxorubicin for sarcoma
– KIT/PDGFRA is one of the client proteins of HSP90 which maintains the conformation and activity ofconformation and activity of specific proteins in the cell
– IPI-504: phase III trial– CNF2024, 17-DMAG, KOS-
1022 : in phase I trials for1022 : in phase I trials for solid tumors
– 17AAG: in phase I, II trials f t tfor many tumor types
I hibit KIT d t i liT t
Inhibit KIT downstream signaling Targets
– PI3K– PKC theta– AKT: perifosine: AKT inhibitor in phase II trials in p p
combination: glivec + perifosine or sutent + perifosine
– mTOR: phase I/II tiral of RAD001 + glivec in underway in GIST
• Other mTOR inhibitors: Rapamune, CCI779, AP23573– Bcl-2: genasense(antisense) in phase II trial in
combination with glivec
C l iConclusions400 /d f i ti ib i th t d d 1st li 400 mg/d of imatinib is the standard 1st line treatment for metastatic or recurrent GISTs.– Dose adjustment with plasma drug monitoring– Nilotinib and masitinib are challenging
Dose escalation or switching to sunitinib is the standard second line treatment after failure of standard dose imatinib.– Nilotinib is challenging for dose escalation of imatinib
New agents for novel targets are urgently needed for the treatment after failure of both imatinib and sunitinib.