1 An Interactive, Case-Based Approach to Targeted Therapies for GIST An On-Demand Webcast.

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An Interactive, Case-Based Approach to Targeted Therapies for GISTAn On-Demand Webcast

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Case Study

• 64-year-old white woman presents with diffuse abdominal pain

• Previously healthy except for resection of duodenal leiomyoma, 2 decades prior

• CT scan reveals multiple liver and peritoneal masses with no clear primary origin

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Case Study Continues

• Percutaneous liver biopsy reveals CD117+ (KIT+) gastrointestinal stromal tumor (GIST)

• PET is positive in liver and peritoneum

4

Question 1

This patient’s primary tumor is most likely:

a) A new as-yet undetected GIST, a distinct clinical entity from her previous leiomyoma

b) The “leiomyoma” resected 2 decades priorc) A gastrointestinal adenocarcinoma

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GIST Background

• Mesenchymal gut neoplasm now recognized as a distinct clinical entity– Formerly misclassified as smooth muscle tumors

(leiomyomas, leiomyoblastomas, leiomyosarcomas) or nerve-sheath tumors

• Most common mesenchymal tumor ofthe gut

• Likely shares a common ancestor with interstitial cells of Cajal

Mietten M, et al. Virchows Arch. 2001;438:1.

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GIST Epidemiology

• Sites of presentation– Stomach 57%

– Small intestine 33.5%

– Colon/rectum 6.5%

– Retroperitoneum 0.5%

– Omentum/mesentery/other 2.5%

• United States– Annual incidence: 14.5 per million persons—4258

casesa

– Prevalence: 129 per million persons—37,882 cases

aClinically detected and KIT-expressing.Courtesy of Charles D. Blanke, MD.

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KIT

• KIT: normal cellular homologue of viral oncogene

• Product: KIT, a 145-kd transmembrane glycoprotein, member of tyrosine kinase III

family– Protein normally expressed on heme progenitors, mast and germ cells, interstitial cells of Cajal

– Also expressed in a limited range of human cancers, including GISTs

• Activation stimulates cell growth and survival through MAP kinase and PI-3 kinase signaling cascades

• Nearly universal KIT positivity in GISTFletcher CDM, et al. Hum Pathol. 2002;33:459.

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Ligand-Dependent Activation of Wild-Type KIT

Membrane

Cytoplasm

SLF = steel factor (KIT ligand); P = sites of phosphorylation.Courtesy of Charles D. Blanke, MD.

SLFSLF

P

P

P

P

PP

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• Immunohistochemistry for KIT was positive in46 of 49 GISTs (94%)

• 5 of 6 GISTs had mutations in KIT gene

• Mutant forms of KIT are constitutively active

Hirota S, et al. Science. 1998;28:577.

Role of KIT Mutations in GIST

Development

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Gain-of-Function Mutations and KIT(Exon 11)

In-frame mutationof exon 11

Membrane

Cytoplasm

Courtesy of Charles D. Blanke, MD.

P

P

P

P

PP

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Case StudyReview

• Patient has biopsy-confirmed GIST with liver and peritoneal metastases

• The primary tumor was resected 2 decades prior

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Question 2

How would you treat this patient?

a) Dacarbazine, mitomycin, doxorubicin, cisplatin ((D-MAP)

b) Mesna, doxorubicin, ifosfamide, dacarbazine (MAID), or doxorubicin, ifosfamide, dacarbazine (AID)

c) Imatinibd) Sunitinibe) Surgical resection

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• Patient is started on imatinib mesylate 400 mg/d

– Approved as 1st-line treatment for KIT+ unresectable/metastatic malignant GIST; 2002

Gleevec (Imatinib). Package insert. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2006.

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Why Not Chemotherapy?

05

0 0 0

27

5

0

10

20

30

40

50

60

70

80

90

100

Response Rate (%)

Epi/Ifos(N = 6)

HEDa

(N = 21)Pac

(N = ~15)Doxo

(N = ~15)Doce

(N = ~5)MAID

(N = 11)D-MAPa

(N = 21)aDefinitely GISTs

Epi/Ifos = epirubicin/ifosfamide; HED = hydroxyurea, etoposide, dacarbazine;Pac = paclitaxel; Doxo = doxorubicin; Doce = docetaxel; MAID = mesna, doxorubicin, ifosfamide, dacarbazine; D-MAP = dacarbazine, mitomycin, doxorubicin, cisplatin.


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Why Not Surgery?

• Resection of peritoneal recurrence rarely prevents further recurrence

• GIST metastatic to liver tends to be multifocal and diffuse and not amenable to resection– Nearly universal recurrence after partial hepatectomy

• In rare cases of low-volume metastatic disease, primary tumor may be resected followed by use of imatinib

• Surgery may also be considered for imatinib-stabilized disease if all gross disease can be resected

Gold JS, et al. Ann Surg. 2006;244:176.

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Premise of Targeted Therapy

• A precise understanding of the pathogenesis of a tumor will lead to more effective treatments, because of the unique nature of that process

– Treatment should also be less toxic

Druker B. Oncol Spect. 2001;2:534.

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Imatinib Mesylate

• Class: 2-phenylaminopyrimidine• Molecular weight: 589.7 g/mol

C29H31N7O•CH4SO3

• CH3SO3H

Gleevec (imatinib). Package insert. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2006.

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Rationale for Imatinib in GIST

aAll KIT mutants and many PDGFR mutants inhibited as well.PDGFR = platelet derived growth factor receptor.

Receptors Units (IC50 µM)

v-ABL 0.25

p210Bcr-Abl 0.25

p185Bcr-Abl 0.25

TEL-Abl 0.35

PDGFR 0.1a

TEL-PDGFR 0.15

KIT 0.1a

1. Druker BJ, et al. Nat Med. 1996;2:561. 2. Carroll M, et al. Blood. 1997;90:4947.

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Phase I/II Studies of Imatinib in Advanced GISTGroup Phase Dose

(mg/d)N ORR

(%)SD (%)

PD (%)

Other

EORTC1 I 400–1000 35 54a 37 5

Wk Grp2 (B2222)

II 400/600 147 67 16 12 Median OS = 57 mo

EORTC3 II 800 27 71a 18 11 73% PFS at 12 mo

aNo responses in non-GIST sarcomas.EORTC = European Organization for Research and Treatment of Cancer; ORR = overall response rate; SD = stable disease; PD = progressive disease; PFS = progression-free survival; OS = overall survival.1. van Oosterom AT, et al. Eur J Cancer. 2002;38:S83. 2. Blanke CD, et al. J Clin Oncol. 2008;26:620. 3. Verweij J, et al. 8th CTOS; October 31-November 2, 2002. Abstract 19.

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Phase III Studies of Imatinib in GIST

Study N Objectives

Primary Secondary

EORTC 620051

946 PFS ORR, safety,

tolerability

US Intergroup S00332

746 PFS, OS ORR, safety,

tolerability

1. Verweij J, et al. Lancet. 2004;364:1127. 2. Blanke CD, et al. J Clin Oncol. 2008;26:626.

• • Eligibility: metastatic or unresectable KIT+ GIST, measurable or nonmeasurable disease

• Prior chemotherapy allowed

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Phase III Studies of Imatinib in GIST

Schema of EORTC 62005 and US Intergroup S0033

Low-doseimatinib(400 mg/d)

High-doseimatinibProgression Progression

Off-protocoltreatment

CROSSOVER

High-dose imatinib(800 mg/d)

Progression Off-protocol treatment

RANDOMIZATION


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Phase III Studies of Imatinib in GISTResponse

EORTC 620051 US Intergroup S00332

400-mg Group

(%)

800-mgGroup

(%)

400-mg Group

(%)

800-mg Group

(%)

Complete response

5 6 5 3

Partial response

45 48 40 42

Stable disease

32 32 25 22

Progressive disease

13 9 12 10


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MetaGIST Meta-analysis of Phase III Imatinib Studies

Progression-Free Survival

Van Glabbeke M, et al. 43rd ASCO; June 1-5, 2007. Abstract 10004.

0

5

10

15

20

25

30

35

40

45

50

Med

ian

PF

S (

mo

)

400 mg Imatinib 800 mg Imatinib

19 mo

23 mo

HR = 0.89; P = .04

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Overall Survival

0

10

20

30

40

50

60

70

Median OS (mo)


49 mo 49 mo

HR = 1.00; P = .97


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• The patient undergoes mutational analysis, which shows an exon 9 mutation

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Question 3

Given the exon 9 mutation, the next step would be to:

a) Discontinue all targeted therapiesb) Switch to sunitinibc) Continue imatinib at 400 mgd) Increase imatinib dose to 800 mge) Increase imatinib dose to 1000 mg

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Imatinib Dosing in Metastatic/Inoperable GIST Based on MetaGIST Project

• 400 mg/d should be the starting dose for most patients

• 800 mg/d is clearly more toxic and a dose most patients cannot tolerate

• Patients with exon 9 mutations may benefit more from 800 mg/d

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Imatinib Toxicity in Advanced GIST EORTC 62005

Side Effect400 mg 800 mg

Grade 3 (%)

Grade 4 (%)

Grade 3 (%)

Grade 4 (%)

Granulo-cytopenia

4 3 5 2

Edema 3 0.2 9 0.4

Fatigue 6 — 11 0.2

Rash 2 — 5 0.2

Diarrhea 1 0.2 5 —

Bleeding 3 0.2 6 2

Any 26 6 43 8

Verweij J, et al. Lancet. 2004;364:1127.

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KIT and PDGFRA Mutationsa in GISTs1581 Cases Analyzed at OHSU

Exon 11 (60%)

Exon 9 (9.9%)

Exon 13 (2%)

Exon 17 (1.3%)

KIT

aWild-type (18.6%).

PDGFRA

Exon 12 (1.2%)

Exon 18 (6.4%)

Exon 14 (0.5%)

Exon 8 (1 Case)

Courtesy of Chris Corless, MD.PDGFRA = platelet derived growth factor receptor, alpha polypeptide.

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PFS in KIT Exon 9 Mutants

0

5

10

15

20

25

30

35

40

45

50

Median PFS (mo)


6 mo

19 mo

P = .017


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Rapid and Durable Response to Imatinib in Sample Patient

Pre-imatinib8/16/00

Post-imatinib2/06/01

4/14/05

(2 consistent scans)


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• The patient’s imatinib dose is increased to 800 mg

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Question 4

a) Is the standard of careb) Is not yet FDA approved, but has shown

benefit in a phase III studyc) Has no role due to lack of efficacy in the

adjuvant setting

In primary localized GIST, adjuvant imatinib:

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Phase III Trial of Adjuvant Imatinib in Resected GIST

ACoSOG Z9001—Study Design

Objectives Primary: recurrence-free survival with imatinib in adjuvant setting relative to placebo

Secondary: overall survival, safety

Treatment Imatinib 400 mg/d or placebo for 1 yUpon recurrence, open-label unblinded phase: placebo cross-over to imatinib, imatinib dose increase to 800 mg if on active treatment or imatinib reinitiated at 400 mg/d if they had previously completed imatinib

Inclusion ≥3 cm, KIT+ GISTSurgery within 70 d prior to registration; NED on postoperative CT/MRINo prior imatinib; no other adjuvant therapy

DeMatteo R, et al. 43rd ASCO; June 1–5, 2007. Abstract 10079.Courtesy of Charles D. Blanke, MD.

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Phase III Trial of Adjuvant Imatinib in Resected GIST: ACoSOG Z9001

DeMatteo R, et al. 43rd ASCO; June 1–5, 2007. Abstract 10079.Courtesy of Charles D. Blanke, MD.

Imatinib Placebo P value

Recurrence-free survival rates

n=325 21 events97% at 1 y


P<.001; HR .33 (.20-.53)

Overall survival1-year follow-up

n=325 3 events

n=319 4 events

P<.72; HR .76 (.17-3.4)

Projected Recurrence-Free Survival (by tumor size)

3-6 cm n=128 4 events

100% at 1 y

n=13511 events95% at 1 y

P =.15; HR .44 (.14-1.4)

6-10 cm n=112 9 events

96% at 1 y

n=10521 events80% at 1 y

P = .01; HR .37 (.17-.81)

≥10 cm n=828 events

96% at 1 y


P<.001; HR .19 (.09-.41)

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Other Ongoing Phase III Trials ofAdjuvant Imatinib in GIST

Trial N Regimen Status

EORTC62024

750 Imatinib vs observation,for 24 mo

Active

SSGXVIII 280 Imatinib 400 mg/d,for 12 vs 36 mo

Recruiting

http://www.cancer.gov/clinicaltrials/EORTC-62024. Accessed April 2008.http://clinicaltrials.gov/ct2/show/NCT00116935?term=SSGXVIII&rank=1. Accessed April 2008.

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Imatinib as Neoadjuvant Therapy Rationale

• Few complete responses with imatinib therapy– Most responding lesions have viable cells

• Cytoreduction may improve surgical outcomes

• Potential to increase resectability or reduce the extent of surgery

Eisenberg BL, et al. Expert Opin Pharmacother. 2003;4:869.Eisenberg BL, et al. Ann Surg Oncol. 2004;11:465.

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• PET at 30 days is cold

• Patient progresses diffusely in the liver20 months later (CT and PET)

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ImatinibMechanisms of Potential Resistance

• Resistance can be primary or secondary (following initial response)

• Mechanisms1

– Imatinib-resistant mutations in KIT or PDGFRA kinase domain

– KIT or PDGFRA gene amplification

– Activation of alternative kinase

• Resistance may be evidenced as progression of some lesions but not others– Focal vs general vs novel resistance

1. Fletcher JA, et al. Proc Am Soc Clin Oncol. 2003;22:815. Abstract 3275.

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Question 5

a) Increase imatinib dose

b) Chemotherapy

c) Sunitinib

d) Hospice and supportive care

What is the best option following progression on imatinib?

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Sunitinib (SU11248)

VEGFR2

VEGFR1

VEGFR3

PDGFR

CSF1RKITFLT3

PDGFR

Sutent (sunitinib). Package insert. New York, NY: Pfizer Labs; 2007.

Courtesy of Dr. Demetri and Dr. Casali.

Approved for treatment of GIST after disease progression or intolerance to imatinib; 2006

NH

O

NH

F

H3C

CH3

NH

O

N

CH3

CH3

Inhibits:

RET

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Phase III Trial of Sunitinib in Imatinib-Refractory GIST

Time to Tumor ProgressionP

rog

ress

ion

(%

)

Sunitinib 50 mg (4 wk on/2 wk offx 6 cycles) (N = 243)

Median: 28.9 wk

Placebo (N = 118) Median: 7.0 wk

Hazard ratio = 0.28

P < .0001

Blinded phase

Casali PG, et al. Proc Am Soc Clin Oncol. 2006;24:abstract 9513.

Time (weeks)

100

90

80

70

60

50

40

30

20

10

0

0 13 26 39 52 65 78

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Continuous Daily Dosing of Sunitinib

George S, et al. 43rd ASCO; June 1-5, 2007. Abstract 10015.

aIndependent 3rd-party review (interim analysis).

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Increased Hematologic Toxicity with Continuous Daily Dosing of Sunitinib

Hematologic Laboratory Abnormalities (Any Grade)

Laboratory Abnormalitya

CDD (N = 60)b1

(Present Study)N (%)

ID (N = 202)2

N (%)

Neutrophils 40 (67) 106 (52)

Hemoglobin 42 (70) 124 (61)

Platelets 25 (42) 81 (40)

aMaximum grade, NCI CTCAE v.3.0.bTo date.CDD = continuous daily dosing; ID = intermittent dosing.

1. George S, et al. 43rd ASCO; June 1-5, 2007. Abstract 10015. 2. Demetri GD, et al. Lancet. 2006;368:1329.

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Phase II Study of Sunitinib in Imatinib-Resistant GIST:Analysis by KIT and PDGFRA Mutational Status

Mutation Status n(N = 47)

RECIST Response

Benefit (Response + Stable

>6 Months)

Exon 9 KIT mutation 19 37% 63%

Exon 11 KIT mutation 42 5% 36%

Wild-type 9 N/A 56%

PDGFR 4 N/A 25%

Adapted courtesy of Chris Corless, MD.

PDGFRA = platelet derived growth factor receptor; RECIST = Response Evaluation Criteria in Solid Tumors.

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In vitro Effects of Sunitinib or Imatinib on KIT Exon 11 + Exon 14 or 17 Double Mutants

pKIT = phosphorylated KIT.Heinrich M, et al. 43rd ASCO; June 1-5, 2007. Abstract 10006.

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In vitro Effects of Sunitinib or Imatinib on Kinase Activity of KIT Mutants

SummaryApproximate IC50 (nM)

Mutation(s) Affected Exon(s) 2nd Exon: Function Sunitinib Imatinib

V560D 11 - <50 100

V560D + V654A 11 + 13 ATP BP <100 5000

V560D + T670I 11 + 14 ATP BP <50 10000

V560D + L783V 11 + 16 Unknown <100 100

V560D + D816H 11 + 17 Act. loop ≥1000 5000

V560D + D820G 11 + 17 Act. loop >1000 5000

V560D + N822K 11 + 17 Act. loop >1000 1000

V560D + Y823D 11 + 17 Act. loop >1000 >1000

V560D + A829P 11 + 18 Ext. act. loop >1000 >1000

Act. loop = activation loop; ATP BP = ATP binding pocket; Ext. act. loop = extended activation loop.Heinrich M, et al. 43rd ASCO; June 1-5, 2007. Abstract 10006.

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Investigational Drugs/Targets in GIST

Drug Targets

Motesanib (AMG 706) VEGFR, PDGFR, KIT, RET

Midostaurin (PKC412) PKCNilotinib (AMN107) KIT, PDGFRA

Rapamycin (RAD001) mTOR

Sorafenib (BAY 43-9006) RAF, KIT, VEGFR, PDGFRβ, FLT3, RET

Dasatinib (BMS-354825) Src, KIT, PDGFR

Retaspimycin (IPI-504) Heat-shock protein 90

Oblimersen (G3139) Bcl-2

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Treatment of GISTRemaining Questions

• Is anything better than imatinib up-front?

– Can we test single agents in that setting?

• What can imatinib be combined with?

– Upcoming Intergroup trial will use bevacizumab

• Will we eventually select the best drug(s)

based on mutational analysis?

– We ARE now using mutational status to select the

best dose of imatinib

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Conclusions

• Surgical resection remains the treatment of choice for localized primary GIST

• Imatinib remains the systemic agent of choice in GIST, despite the emergence of resistance in some patients– Initial dose should be 400 mg/d in advanced disease

– Patients with exon 9 mutants should get 800 mg/d

• Sunitinib is the agent of choice for patients who are resistant or intolerant to imatinib

1 An Interactive, Case-Based Approach to Targeted Therapies for GIST An On-Demand Webcast.

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