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.