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




                             1
                 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




                                                  2
         Case Study Continues


• Percutaneous liver biopsy reveals
  CD117+ (KIT+) gastrointestinal stromal
  tumor (GIST)
• PET is positive in liver and peritoneum




                                            3
                  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 prior
c) A gastrointestinal adenocarcinoma




                                                 4
                                 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 of
    the gut
  • Likely shares a common ancestor with interstitial
    cells of Cajal

Mietten M, et al. Virchows Arch. 2001;438:1.                5
                                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.                             6
 Courtesy of Charles D. Blanke, MD.
                                                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 GIST

Fletcher CDM, et al. Hum Pathol. 2002;33:459.
                                                                             7
        Ligand-Dependent Activation of Wild-Type
                         KIT



                                               SLF         SLF




                                                                     Membrane

                                      P                          P
                                          P                      P
                                                                     Cytoplasm
                                      P                          P


SLF = steel factor (KIT ligand); P = sites of phosphorylation.              8
Courtesy of Charles D. Blanke, MD.
                        Role of KIT Mutations in GIST
                                         Development

         • Immunohistochemistry for KIT was positive in
           46 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.                     9
              Gain-of-Function Mutations and KIT
                                     (Exon 11)




In-frame mutation                                    Membrane
of exon 11
                                P                P
                                 P           P       Cytoplasm
                                P                P


Courtesy of Charles D. Blanke, MD.                         10
                 Case Study
                    Review


• Patient has biopsy-confirmed GIST with liver
  and peritoneal metastases
• The primary tumor was resected 2 decades
  prior




                                                 11
                 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) Imatinib
d) Sunitinib
e) Surgical resection
                                                12
                              Case Study Continues

     • 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.

                                                                                             13
                                        Why Not Chemotherapy?
                    100
                    90
                    80
Response Rate (%)




                    70
                    60
                    50
                    40
                    30                                                                27
                    20
                    10                    5                                                         5
                              0                       0         0         0
                     0
                           Epi/Ifos    HEDa         Pac        Doxo     Doce        MAID         D-MAPa
                           (N = 6)    (N = 21)   (N = ~15)   (N = ~15) (N = ~5)    (N = 11)      (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.                                 14
Courtesy of Charles D. Blanke, MD.
                                   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.
                                                                        15
                      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.
                                                    16
                                   Imatinib Mesylate




                                                        • CH3SO3H


                                              C29H31N7O•CH4SO3


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

Gleevec (imatinib). Package insert. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2006.   17
                       Rationale for Imatinib in GIST

                     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

aAllKIT mutants and many PDGFR mutants inhibited as well.
PDGFR = platelet derived growth factor receptor.
                                                                                      18
1. Druker BJ, et al. Nat Med. 1996;2:561. 2. Carroll M, et al. Blood. 1997;90:4947.
 Phase I/II Studies of Imatinib in Advanced GIST
Group             Phase          Dose            N      ORR          SD         PD             Other
                                (mg/d)                  (%)          (%)        (%)

EORTC1                I       400–1000           35       54a         37          5



Wk Grp2              II         400/600         147       67          16         12       Median OS =
(B2222)                                                                                     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.                                   19
               Phase III Studies of Imatinib in GIST

                      Study                  N                       Objectives

                                                             Primary           Secondary

                 EORTC                      946                 PFS                ORR,
                 620051                                                           safety,
                                                                                tolerability
                 US                         746              PFS, OS               ORR,
                 Intergroup                                                       safety,
                 S00332                                                         tolerability

     • Eligibility: metastatic or unresectable KIT+ GIST, measurable or
       nonmeasurable disease
     • Prior chemotherapy allowed
1. Verweij J, et al. Lancet. 2004;364:1127. 2. Blanke CD, et al. J Clin Oncol. 2008;26:626.
                                                                                               20
               Phase III Studies of Imatinib in GIST
           Schema of EORTC 62005 and US Intergroup
                          S0033

                                                       C
                                                       R
    R                                                  O
    A            Low-dose                              S
                                                                  High-dose                        Off-protocol
    N             imatinib       Progression           S                         Progression
                                                                   imatinib                         treatment
    D            (400 mg/d)                            O
    O                                                  V
    M                                                  E
    I                                                  R
    Z
    A
    T
    I            High-dose
    O             imatinib                        Progression                        Off-protocol treatment
    N            (800 mg/d)




1. Verweij J, et al. Lancet. 2004;364:1127. 2. Blanke CD, et al. J Clin Oncol. 2008;26:626.              21
               Phase III Studies of Imatinib in GIST
                                               Response

                                     EORTC 620051                       US Intergroup S00332

                                400-mg               800-mg              400-mg               800-mg
                                 Group                Group               Group                Group
                                  (%)                  (%)                 (%)                  (%)
        Complete                     5                   6                   5                  3
        response
        Partial                     45                   48                 40                  42
        response
        Stable                      32                   32                 25                  22
        disease
        Progressive                 13                   9                  12                  10
        disease

1. Verweij J, et al. Lancet. 2004;364:1127. 2. Blanke CD, et al. J Clin Oncol. 2008;26:626.
                                                                                                       22
                            MetaGIST Meta-analysis of Phase III
                                    Imatinib Studies
                                  Progression-Free Survival
                       50
                       45
                                       HR = 0.89; P = .04
                       40
     Median PFS (mo)




                       35
                       30                                           23 mo

                       25              19 mo
                       20
                       15
                       10
                        5
                        0
                                    400 mg Imatinib        800 mg Imatinib

                                                                             23
Van Glabbeke M, et al. 43rd ASCO; June 1-5, 2007. Abstract 10004.
                          MetaGIST Meta-analysis of Phase III
                                  Imatinib Studies
                                       Overall Survival

                     70                     HR = 1.00; P = .97
                     60
                                       49 mo                        49 mo
    Median OS (mo)




                     50

                     40

                     30

                     20

                     10

                     0
                                  400 mg Imatinib          800 mg Imatinib
                                                                             24
Van Glabbeke M, et al. 43rd ASCO; June 1-5, 2007. Abstract 10004.
             Case Study Continues


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




                                                       25
            Question 3
Given the exon 9 mutation, the next step
would be to:

a) Discontinue all targeted therapies
b) Switch to sunitinib
c) Continue imatinib at 400 mg
d) Increase imatinib dose to 800 mg
e) Increase imatinib dose to 1000 mg




                                           26
  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



                                                   27
                 Imatinib Toxicity in Advanced GIST
                                            EORTC 62005

                                           400 mg                800 mg
         Side Effect
                               Grade 3          Grade 4   Grade 3     Grade 4
                                 (%)              (%)       (%)         (%)
         Granulo-                   4               3       5             2
         cytopenia
         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.                                        28
               KIT and PDGFRA Mutationsa in GISTs
                         1581 Cases Analyzed at OHSU
         KIT                         PDGFRA




                            Exon 8 (1 Case)
                             Exon 9 (9.9%)

                             Exon 11 (60%)                             Exon 12 (1.2%)

                             Exon 13 (2%)                              Exon 14 (0.5%)

                             Exon 17 (1.3%)                            Exon 18 (6.4%)

aWild-type   (18.6%).
PDGFRA = platelet derived growth factor receptor, alpha polypeptide.                    29
Courtesy of Chris Corless, MD.
                           MetaGIST Meta-analysis of Phase III
                                   Imatinib Studies
                                 PFS in KIT Exon 9 Mutants
                      50
                      45                                    P = .017

                      40
    Median PFS (mo)




                      35
                      30
                      25                                            19 mo

                      20
                      15
                                           6 mo
                      10
                      5
                      0
                                    400 mg Imatinib          800 mg Imatinib
                                                                               30
Van Glabbeke M, et al. 43rd ASCO; June 1-5, 2007. Abstract 10004.
       Rapid and Durable Response to Imatinib in
                   Sample Patient


                         Pre-imatinib
                              8/16/00



                       Post-imatinib
                             2/06/01
                                     4/14/05
                       (2 consistent
                             scans)
                                               31
Courtesy of Charles D. Blanke, MD.
     Case Study Continues


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




                                   32
                   Question 4

In primary localized GIST, adjuvant imatinib:

a) Is the standard of care
b) Is not yet FDA approved, but has shown
   benefit in a phase III study
c) Has no role due to lack of efficacy in the
   adjuvant setting




                                                33
             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 y
                            Upon 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+ GIST
                            Surgery within 70 d prior to registration; NED on
                            postoperative CT/MRI
                            No prior imatinib; no other adjuvant therapy

DeMatteo R, et al. 43rd ASCO; June 1–5, 2007. Abstract 10079.                             34
Courtesy of Charles D. Blanke, MD.
             Phase III Trial of Adjuvant Imatinib in
               Resected GIST: ACoSOG Z9001
                                   Imatinib             Placebo               P value

     Recurrence-free            n=325           n=319        P<.001; HR .33 (.20-.53)
      survival rates          21 events       62 events
                             97% at 1 y       83% at 1 y
     Overall survival           n=325           n=319          P<.72; HR .76 (.17-3.4)
     1-year follow-up          3 events        4 events
                    Projected Recurrence-Free Survival (by tumor size)

           3-6 cm                   n=128                n=135      P =.15; HR .44 (.14-1.4)
                                   4 events            11 events
                                 100% at 1 y           95% at 1 y
          6-10 cm                   n=112                n=105      P = .01; HR .37 (.17-.81)
                                   9 events            21 events
                                  96% at 1 y           80% at 1 y
           ≥10 cm                    n=82                 n=76      P<.001; HR .19 (.09-.41)
                                   8 events            30 events
                                  96% at 1 y           67% at 1 y



DeMatteo R, et al. 43rd ASCO; June 1–5, 2007. Abstract 10079.                                   35
Courtesy of Charles D. Blanke, MD.
                   Other Ongoing Phase III Trials of
                      Adjuvant Imatinib in GIST


           Trial                 N                    Regimen                        Status
           EORTC                750          Imatinib vs observation,                Active
           62024                                    for 24 mo

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




                                                                                                36
http://www.cancer.gov/clinicaltrials/EORTC-62024. Accessed April 2008.
http://clinicaltrials.gov/ct2/show/NCT00116935?term=SSGXVIII&rank=1. Accessed April 2008.
                 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.   37
Eisenberg BL, et al. Ann Surg Oncol. 2004;11:465.
             Case Study Continues

• PET at 30 days is cold
• Patient progresses diffusely in the liver
  20 months later (CT and PET)




                                              38
                                              Imatinib
                   Mechanisms 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

                                                                             39
1. Fletcher JA, et al. Proc Am Soc Clin Oncol. 2003;22:815. Abstract 3275.
                Question 5
What is the best option following
progression on imatinib?

a) Increase imatinib dose
b) Chemotherapy
c) Sunitinib
d) Hospice and supportive care




                                    40
                           Sunitinib (SU11248)
                                 O
                           H3C
                                     N
                                     H
                                  CH3      N
            F                N
                             H
                            O         C        C
                       N              H3       H3
                       H


   Approved for treatment of GIST after                    Inhibits:
   disease progression or intolerance to
   imatinib; 2006                                                  VEGFR1 PDGFRa
                                                                   VEGFR2 PDGFRb
                                                                   VEGFR3 CSF1R
                                                                          KIT
Sutent (sunitinib). Package insert. New York, NY: Pfizer Labs; 2007.
Courtesy of Dr. Demetri and Dr. Casali.
                                                                          FLT3
                                                                          RET      41
             Phase III Trial of Sunitinib in Imatinib-
                        Refractory GIST
                                            Time to Tumor Progression
                                            Blinded phase
                                                  Sunitinib 50 mg (4 wk on/2 wk off     Median: 28.9 wk
                                                  x 6 cycles) (N = 243)
                                                  Placebo (N = 118)                     Median: 7.0 wk
                                  100
                Progression (%)




                                  90

                                  80
                                  70
                                                        Hazard ratio = 0.28
                                  60                    P < .0001
                                  50
                                  40

                                  30
                                  20
                                  10
                                   0

                                        0    13    26        39      52       65   78


                                                        Time (weeks)
                                                                                                     42
Casali PG, et al. Proc Am Soc Clin Oncol. 2006;24:abstract 9513.
          Continuous Daily Dosing of Sunitinib




aIndependent 3rd-party review (interim analysis).
                                                              43
George S, et al. 43rd ASCO; June 1-5, 2007. Abstract 10015.
              Increased Hematologic Toxicity with
              Continuous Daily Dosing of Sunitinib
            Hematologic Laboratory Abnormalities (Any Grade)

Laboratory                                        CDD (N = 60)b1                             ID (N = 202)2
Abnormalitya                                     (Present Study)
                                                      N (%)                                         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.

                                                                                                              44
              Phase II Study of Sunitinib in
          Imatinib-Resistant GIST:
Analysis by
           KIT and PDGFRA Mutational Status
     Mutation Status                             n               RECIST              Benefit (Response
                                                                Response                 + Stable
                                            (N = 47)
                                                                                        >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%

PDGFRA = platelet derived growth factor receptor; RECIST = Response Evaluation Criteria in Solid Tumors.
Adapted courtesy of Chris Corless, MD.
                                                                                                           45
    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.




                                                                46
         In vitro Effects of Sunitinib or Imatinib on
                Kinase Activity of KIT Mutants
                                              Summary
                                                                                  Approximate 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.                                             47
Investigational Drugs/Targets in GIST

          Drug                      Targets

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

Midostaurin (PKC412)      PKC
Nilotinib (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


                                                     48
              Treatment of GIST
              Remaining 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                              49
                   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
                                                          50

				
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