Gastrointestinal Stromal TumorGIST

New Therapeutic Approaches

Prof. Mohamed AbdullaA. Professor of Clinical OncologyKasr El-Aini School of Medicine

Cairo University.

IMC – Cairo – October 30th, 2007

GIST: Definition

Mesenchymal (connective tissue) neoplasms

Located primarily in the GI tract, omentum, and mesentery

0.2% of all GI tumors

80% of GI sarcomas

Usually stain positive for KIT

GIST: Epidemiology

An estimated 10-20 cases per million of GIST are diagnosed in the United States each year– 5000-6000 cases per year are diagnosed in the

United States2

Incidence in the Netherlands3 and Sweden: 12.7-14.5 cases per million

Highest incidence among group aged 50-65 years– Similar male/female incidence, although some reports suggest

higher incidence in men

Gene mutation key event in Gene mutation key event in malignant transformation in most malignant transformation in most casescases1,21,2

– KITKIT: 80%-85%: 80%-85%– PDGFRA:PDGFRA: 5%-7% 5%-7%– Wild TypeWild Type: 12%: 12%

Mutation results in expression of Mutation results in expression of abnormal, constitutively activated abnormal, constitutively activated receptor tyrosine kinase activityreceptor tyrosine kinase activity

GIST: PathogenesisGIST: Pathogenesis

GIST: Pathogenesis GIST: Pathogenesis (Continued)(Continued)

Extracellular domain (exon 9)

Transmembrane domainJuxtamembrane domain (exon 11)

ATPTyrosine kinase domain (exon 13/14)

Kinase insert

Tyrosine kinase domain II (exon 17)

= Mutation site= Imatinib contact point

ProliferationSurvivalAdhesionInvasionMetastasisAngiogenesis

In GIST where mutant KIT is expressed, ATP-dependent signal transduction occurs in the absence of SCF1-3

Histopathology

At diagnosis, GIST generally is 2-30 cmAt diagnosis, GIST generally is 2-30 cm11

GIST can be classified into 3 broad categoriesGIST can be classified into 3 broad categories22

– Spindle-cell type (70%)Spindle-cell type (70%)– Epithelioid-cell type (20%)Epithelioid-cell type (20%)– Mixed spindle-cell and epithelioid-cell type (nested morphology) (10%)Mixed spindle-cell and epithelioid-cell type (nested morphology) (10%)

Spindle cell Epithelioid cell Mixed morphology

Historical Classification of GISTs as Other Soft-Tissue Sarcomas

Nilsson B et al. Cancer. 2005;103:821-829.

GIST

LeiomyomaLeiomyosarcoma

Leiomyoblastoma

Other

7%

13%

18%

34%

28%

N = 600

A retrospective Swedish study determined that 60% of GI tumors now identified as GIST originally were classified as other tumors

Immunohistochemistry: CD117 Positivity Is a Reliable Marker of GIST

Spectrum of staining for KIT (CD117) in GIST

Approximately 95% of GISTs stain positive for CD117 (KIT)1

Of those that do not, about 1/3 harbor a mutation in PDGFRA2

Variable Pattern of KIT (CD117) Staining in GIST

Differential Diagnosis of KIT-Undetectable Tumors Suspected to be GIST

KIT (CD117

)CD34SMADesmi

nS-

100

GIST+) +60%-70%() +30%-

40%(Very rare

+)5%(

Smooth muscle tumor

−) +10%-15%(++Rare

Schwannoma

−)usually

Antoni B(−−+

Fibromatosis

Disputed*

Rare+Rare cells

−

KIT (CD117)is not detected in ~5% of GIST Immunohistology for other protein markers or genetic analysis for KIT and

PDGFRA may support a GIST diagnosis Suspected GISTs without evidence of KIT (CD117) expression should be

referred to an experienced GIST pathologist

Emerging Marker: PKCθ

GIST×10

KIT PKCθ

85%-100% of GISTs stain positive for PKCθ Other similar mesenchymal neoplasias do not stain positive

for PKCθ3

GIST: Risk Assessment Accurate assessment of risk of aggressive

malignant behavior in GIST poses a challenge

Morphologic features most predictive of outcome– Mitotic rate – Tumor size

Mutational status is useful in predicting treatment response and risk of progression

Risk of Aggressive Tumor Behavior

Size(cm)

Mitotic Count (HPF)

Very low risk<2<5/50

Low risk2-5<5/50

Intermediate risk

<5 5-10

6-10/50<5/50

High risk>5>10Any size

>5/50 Any mitotic rate>10/50

All GISTs should be considered to have potential for malignant behavior1,2

Overall Survival by Risk Group

Nilsson B et al. Cancer. 2005;103:821-829.  2005 American Cancer Society.

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Est

imat

ed P

rop

ort

ion

Su

rviv

ing

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Years Since Diagnosis

Normal population

Intermediate

HighOvertly malignant

Very low

Low

GIST Risk Groups

Circumstances of GIST Detection

Incidental

Symptomatic

Autopsy

69%21%

10%

Approximately 1/3 of GISTs are asymptomatic

Common Tumor Sites

ColonOther (rectum, esophagus, mesentery, retroperitoneum)

50%

10% 15%

25%Small intestineStomach

GIST may occur anywhere along the GI tract or elsewhere in the abdomen or retroperitoneum

Clinical Presentation

Most patients present with nausea, vomiting, pain, weight loss, palpable tumor masses, and bleeding leading to anemia2

Average duration of presenting symptoms is 4-6 months2

Symptoms of GIST at Diagnosis

SymptomOccurrence Rate

Abdominal pain

50%-70%

GI bleeding50%

Chemotherapy, Radiation, and Surgery in GIST

Chemotherapy Ineffective in sarcomas Response limited: ~5% Survival: no impact

Surgery Principal treatment for resectable primary GIST

Radiation Results in injury to adjacent organs Tumors exhibit radioresistance Possible therapeutic role in rectal

tumors

Poor Historical Survival Rates During thePre-Imatinib Era

Months After Diagnosis

Pro

po

rtio

n S

urv

ivin

g

1.0

0.8

0.6

0.4

0.2

0

0 12 24 36 48 60

GIST

Leiomyosarcoma

P < 0.05

GIST: Current Treatment Options

Surgery

Treatment of choice for

localized primary resectable

GIST

Imatinib

First-line treatment of

malignant unresectable or

metastatic GIST1,2

Surgery for Primary Tumors

RisksRisks

Rupture of tumor increases risk of

Bleeding

Dissemination

WarningsWarnings

Segmental resection of stomach or intestine

Margins should be clear No benefit in wide margins

Inspect abdomen for metastases Peritoneal surfaces Liver

Goal of SurgeryGoal of Surgery

Complete gross resection of tumor with pseudocapsule intact

GIST often can be lifted from surrounding organs

Survival Following Surgical Treatment

of Primary GIST

Adapted with permission from DeMatteo RP et al. Ann Surg. 2000;231:51-58.

GIST Recurrence After Surgery Recurrence of GIST following surgery is common

– Majority of high-risk patients experience recurrence – Median time to recurrence is 2 years

Only 10% of patients remain disease-free after extended follow-up

5-year survival rates are ~30%-60%

Investigational protocols are under way, with the goal of reducing the rate of recurrence after resection

Recurrent disease should be treated as metastatic disease

Primary GIST: Risk Factors for Recurrence After Surgery

0

0.25

0.50

0.75

1.0

0 20 40 60 80

<5 cm

5-10 cm

>10 cm

P = 0.03

Months

RF

S0

0.25

0.50

0.75

1.0

20 40 60 80Months

3 mitoses/30 HPF

>3 to 15 mitoses/30 HPF

>15 mitoses/30 HPFP = 0.0001

0

RF

S

Rates of RFS were predicted by mitotic index and tumor size

Surgery for Recurrent or Metastatic GIST Recurrent GIST should be treated as metastatic

disease– Imatinib indicated as first-line treatment in both instances

Potential role for surgery after maximum response to imatinib mesylate

Resection of imatinib mesylate–resistant clones (under investigation)

Surgery for liver metastases– Often unsuitable for multifocal disease in liver– Consider RFA or hepatic artery embolization

Complementary use of surgery may benefit patients whose disease is stable on imatinib therapy

Imatinib

First-Line Treatment of Unresectable or Metastatic GIST

Indicated for the treatment of adult patients with KIT- (CD117-) positive unresectable or metastatic malignant GIST

Studies of Imatinib Therapy in GIST

PilotPhase 1Phase 2Phase 3

Pilot Study Exploratory Study (N = 1)

Dose-Finding Study (N = 40)

US Finland B2222 Open-Label Study (N = 147)

EORTC 62005 Randomized Study (N = 946)

1 patient 400 mg/d

Efficacy and safety

400 vs 1000 mg/d

Metastatic GIST (EORTC)

Efficacy and safety

400 vs 600 mg/d Metastatic or

unresectable GIST

Efficacy and safety

400 vs 800 mg/d Metastatic or

unresectable KIT-positive GIST

EORTC Phase 2 study (N = 51)

US Intergroup S0033 Study (N = 746)

Efficacy and safety

Advanced or metastatic GIST and other soft-tissue sarcomas

Efficacy and safety

400 and 800mg/d Metastatic or

unresectable KIT-positive GIST

Phase 3 Trials: Overview

Two Parallel Phase 3 Studies of Imatinib in GIST

US Intergroup S0033 study

US and Canada

(N = 746)

EORTC 62005 study

Europe and Australia/Asia

(N = 946)

Aim: Efficacy and safety evaluation of imatinib 400 vs 800 mg/d in metastatic or unresectable KIT-positive GISTMajor findings PFS at 3 years follow-up not

significantly different with 800-mg vs 400-mg dose

Similar rates of response for the 2 dosing arms 36% of 400-mg/d nonresponders benefited from 800-mg/d dose2

In general, 800 mg/d is well tolerated, with higher rates of grade 3/4 toxicities

Phase 3 EORTC 62005 Study: PFS (Primary End Point)

Response Rates of Phase 3 Studies:EORTC 62005 and US Intergroup S0033 Study

Best Overall Response (ITT analysis)

EORTC 62005 Study(N = 461)

US Intergroup S0033 Study (N = 462)

Pat

ien

ts,

%

5 6

4548

32 32

139

3 3

45 45

27 26 2625

Imatinib 400 mg/d

Imatinib 800 mg/d

US Intergroup S0033 and EORTC 62005 Studies: Similar PFS Regardless of Dose Administered

Months

0 6 12 18 24 300

10

20

30

40

50

60

70

80

90

100

Overall Logrank test: Intergroup S0033 P = 0.026EORTC 62005 P = 0.13

400 mg800 mg

400 mg800 mg

EORTC 62005

Intergroup S0033

36

Phase 3 Studies: Response Rates After Phase 3 Studies: Response Rates After Crossover to Imatinib Crossover to Imatinib 800 mg/d mg/d

Pat

ien

ts,

%

02.3

27.1

59.4

010203040506070

CR PR SD PD AI

62005 Trial62005 Trial11

06

32

48

13

0

10

20

30

40

50

60

CR PR SD PD

Pat

ien

ts,

%

AI

S0033 TrialS0033 Trial22

One third of patients benefited from dose increase at progression

Phase 3 Studies: Conclusions Two parallel phase 3 studies compared

imatinib 400 mg/d and 800 mg/d in patients with metastatic unresectable GIST

– US Intergroup S0033 study (N = 746)– EORTC 62005 study (N = 946)

EORTC 62005 study results1

– According to standard RECIST criteria, no significant difference in ORR between standard-dose and high-dose groups (50% vs 54%, respectively)

– No significant advantage in PFS at 800 mg/d (P = 0.108)2

US Intergroup S0033 study results3

– Doses similar in confirmed ORR (both 48%)– Similar 2-year PFS for standard dose vs high dose (47% vs

52%, respectively; P = 0.13)

Discontinuation of Imatinib Increases Risk of GIST Progression

Pa

tie

nts

, %

Months After Randomization1614121086420

100

80

60

40

20

0

Stop therapy (n = 25)Median PFS: 6 months

Continuous therapy (n = 23)

P = 0.0001

Study BFR14

Patients who achieved clinical benefit after 12 months were randomized to continue or stop imatinib therapy

Stop-therapy arm was discontinued because of high rates of disease progression

Reintroduction of imatinib enabled tumor control in all those patients