Small Molecule Kinase Inhibitors

in CML and GIST Tumors

GIST Tumor After 8 Weeks GleevecA

 Monoclonal Abs vs. Small MoleculesD,E,K
Small Molecule Monclonal Antibodies
(e. g. Gleevec) (e. g. Herceptin)

Size 400 daltons 150,000 daltons

Targets One or more tyrosine kinase(s) Extracellular antigen
(e. g. ABL, KIT, PDGFRA) (e. g. EGFR2 tyrosine kinase)

Proposed Inhibits intracellular signaling by Antigen dependent cellular cytotoxicity

Mechanisms inhibiting kinase activity Inhibit intracellular signaling
Of Action (Inhibit PI3K, augment PTEN)
Induce (G1) cell cycle arrest
Inhibit angiogenesis
 FDA Approved Small Molecule Kinase InhibitorsB
Generic Trade Approved Use Distributor 1st Approval

dasatanib Sprycel CML Bristol Myers 6/28/2006

NSCLC – Locally advanced or metastatic after
failure of at least one prior chemotherapy regimen
erlotinib Tarceva Pancreatic cancer – in combination with OSI 11/18/2004
gemcitabine for the first-line treatment of patients
with locally advanced, unresectable disease
NSCLC – Monotherapy for locally advanced or
gefitinib Iressa metastatic disease after failure of both platinum- AstraZenca 5/5/2003
based and docetaxel chemotherapies*
Ph+ CML – initial therapy for chronic phase,
accelerated phase, blast crisis, after interferon alpha
failure, and after PSCT failure
imatinib mesylate Gleevec Novartis 5/10/2001
GIST tumors – Unresectable or metastatic Kit
(CD117) positive *
Single agent for the treatment of multiple indications
Renal cell carcinoma – For the treatment of patients
sorafenib Nexavar Bayer 12/20/2005
with advanced disease
GIST tumors – after imatinib failure or intolerance
sunitinib maleate Sutent Pfizer 1/26/2006
renal cell carcinoma – Advanced disease*

* Accelerated Approval (clinical benefit not established)

Spectrum of Tyrosine Kinase InhibitionK
 Topics
1. Proof of principle: Imatinib in chronic
phase CML
2. Targeting resistance: Dasatinib in chronic
phase CML
3. Success in a solid tumor: Imatinib and
Sunitinib in advanced and metastatic
GIST tumors
 Approach
1. Review disease
2. Outline rationale for first generation drug
3. Review clinical trial data
4. Outline rationale for second generation drug
5. Review clinical trial data
 CML: A review H

• 15%–20% of all cases of leukemia

• 1 to 2 cases per 100,000 per year.
• Median 50 and 60 years of age but large
range
• Distinct phases
– Chronic
– Accelerated
– Blast
 Chronic Phase CMLS
• Symptoms if present
– Systemic – fatigue, malaise, wt loss, sweating
– Abdominal fullness/pain due to splenomegaly
– Bleeding due to platelet dysfunction
• Exam
– Splenomegaly (hepatomegaly, LAD)
• Labs
– Anemia
– Leukocytosis (WBC > 100k)
• Range of cells from neutrophil series – blasts to segs
• Absolute eosinophila and basophlia
– Thrombocytosis (plts > 600k)
• Diagnosis
– Demonstration of BCR-ABL fusion gene
• Time to progression
– Average 3-5 years before imatinib
 Accelerated Phase CML S

• WHO criteria (1 or more):

– 10-19% blasts in marrow or periphery
– > 20% basophils in periphery
– < 100k plts or > 1M plts
– Counts difficult to control with medications
– Further impaired leukocyte differentiation
– Progressive splenomegaly
• Time to progression – 3 to 18 mos
 Blast Phase CML S

• > 20 % blasts in marrow or periphery

• Clusters of blasts on BM bx
• Extramedullary blastic infiltrates
• Median survival 6-12 months
 Conventional Therapy for
Chronic Phase CML
• Chemotherapy including interferon alpha
plus cytarabine
• Allogeneic BMT
– Potentially curative
– Better survival in young
– High first year mortality
 CML: The Philadelphia
ChromosomeH
• Bcr-Abl present in 95% of patients with CML,
sufficient alone to cause CML in animal models
• Bcr-Abl is a constitutively activated tyrosine
kinase and its activity is dependent on tyrosine
kinase activity of the Abl portion
• Bcr-Abl activity
– Increases proliferation
– Inhibits apoptosis
– Enhances genetic instability
CML: The Philadelphia
ChromosomeI
 Imatanib
“Imatinib mesylate…the first commercially
available small molecule tyrosine kinase
inhibitor…is proof-of-principle that
molecularly targeted therapy can work.”

Charles Sawyers, 2001C

CML: The Philadelphia ChromosomeK
Development of Imatinib I

Random screening of puported

Abl, PDGF-R inhibitors
(2-phenylaminopyrimidines)

Identification of lead compound (a weak PDGF-R)

Synthesis of compounds with

enhanced PDGFR, Abl inhibition

Potent v-Abl and PDGF-R

inibitors identified including STI
571 (Imatinib)

In vitro and animal studies

 Phase 3 Trial -- Patients G

• 1106 enrolled
• Ages 18 to 70
• Within 6 months of diagnosis
• Daily SC IFN + 10 d ARA-C/mo vs
Imatinib
• Many chemo patients crossed over or
dropped out once Imatinib on market
Reasons for Discontinuation / Cross Over G
Reasons for Discontinuation of Gleevec
versus Interferon Alfa plus Cytarabine G
 Early Phase III Results Demonstrated Superior Response to Imatinib
(Median Follow Up 14 mos).E

Imatinib 400 mg Interferon + Ara-C

Complete hematologic response 96% 67%*
Major cytogenetic response 83% 20%*
Complete cytogenetic response 68% 7%*
Intolerance leading to d/c Tx 0.7% 23%*
Progression to accelerated or blast
phase 1.5% 7%*
*P < 0.001
Complete hematologic response (normalization of CBC)
Major cytogenetic response (Ph+ metaphases < 35%)
Complete cytogenetic response (no Ph+ metaphases)
Response Rates Improved with TimeG
Initial Response Predicts Disease-
Free SurvivalG
Initial Response Predicts Disease-
Free SurvivalG
 Chronic Phase CML Survival
2 Separate Studies
CML Related

All Deaths

1995-2005
Interferon  + ARA-C
(prior data) 1984-1994

Gleevec (Intention to Treat). Allogeneic BMT.

Druker et al. NEJM 355 (23): 2408 G Weisser et al Ann Hematol. 2007
Feb;86(2):127-132.
F
Imatinib Grade 3 and 4 Adverse Events G
 Imatinib Adverse Events
(Common)G
• Edema (including peripheral and periorbital edema)
(60%)
• nausea (50%)
• muscle cramps (49%)
• musculoskeletal pain (47%)
• diarrhea (45%)
• rash and other skin problems (40%)
• fatigue (39%)
• abdominal pain (37%)
• headache (37%)
• joint pain (31%)
 Imatinib in CML – Conclusions
• Effective
• Better tolerated than chemo
• Improved response over time
• Early response predicts outcome
 Dasatanib (Sprycel ) – Rationale
® J

• 30% discontinue imatinib due to

unsatisfactory therapeutic effects or
toxicity.
• High dose imatinib (800 mg/day) can
overcome resistance but patients may not
tolerate and responses are short term.
Sources of Imatinib Resistance K

• BCR-ABL gene mutations

– Impeded contact between drug and target
– Impede BCR-ABL inactive conformation
 Sources of Imatinib Resistance K

• BCR-ABL independent pathways (src)

– Src inhibition decreases proliferation and progression
– Resistant cells have low BCR-ABL activity, high src activity
Sources of Imatinib Resistance K

• BCR-ABL overexpression/amplification
• Drug binding to alpha-1 acid glycoprotein
• Increased drug efflux through MDR gene
 Characteristics of Dasatanib K

• Multiple targets including BCR-ABL, Src family

• Targets sources of resistance
– Amplification
• 325 times more potent than imatinib
– Autonomous Src activity
• Inhibits both BCR-ABL and Src
– Loss of inactive conformation
• Binds active and inactive conformation
• Binds all but ATP-binding pocket mutant
 Dasatinib or high-dose imatinib for
chronic-phase chronic myeloid leukemia
after failure of first-line imatinib: a
randomized phase-II trialJ
Kantarjian H, Pasquini R, Hamerschlak N, Rousselot P, Holowiecki J,
Jootar S, Robak T, Khoroshko N, Masszi T, Skotnicki A, Hellmann A,
Zaritsky A, Golenkov A, Radich J, Hughes T, Countouriotis A, Shah
N.

Blood First Edition Paper, prepublished online February 22, 2007; DOI
10.1182/blood-2006-11-056028
 Prior Experience w/ ImatinibJ
Characteristic Dasatinib (N=101) High-dose imatinib (N=49)

Duration of prior imatinib therapy – n (%)

<1 yr 12 (12) 5 (10)
1-3 yr 44 (44) 29 (59)

>3 yr 45 (45) 15 (31)

Prior response to imatinib – n (%)

CHR 93 (92) 47 (96)

CCyR 15 (15) 4 (8)

PCyR 13 (13) 10 (20)
Reason for imatinib resistance* – n (%)
Loss of MCyR 21 (21) 14 (29)

Loss of CHR 24 (24) 15 (31)

Increasing WBC 4 (4) 2 (4)
No CHR after 3 months 3 (3) 2 (4)

No CyR after 6 months 39 (39) 16 (33)

No MCyR after 12 months 39 (39) 24 (49)
Mutation, Treatment and Response Status J
Characteristic Dasatinib (N=101) High-dose imatinib (N=49)

Mutation status – n/N (%)

BCR-ABL mutation 41/92 (45) 11/46 (24)

Treatment history – n (%)

Hydroxyurea / anagrelide 97 (96) 46 (94)

Interferon-α 74 (73) 33 (67)

Chemotherapy 39 (39) 18 (37)

Bone marrow transplant 7 (7) 2 (4)

Response status – n (%)

Patients in CHR at entry 51 (50) 27 (55)

Patients in MCyR at entry 6 (6) 0

Response to Dasatinib vs. High Dose ImatinibJ
Dasatinib Imatinib
Maintained CHR 100% 89%
Attained CHR 86% 73%
Attained MCyR at 36% 29%*
12 weeks
Attained CCyR at 22% 8%**
12 weeks
Attained MCyR at 52% 33%***
15 months
Attained CCyR at 40% 16%****
15 months

*NS **p=0.041 ***p=0.023 ****p=0.004

Degree of Improvement J
Bcr-Abl Mutations – Imatinib vs. Dasatinib J
MCyR May Be More Durable with Dasatinib J
Time to Treatment Failure J
Dasatinib: Progression Free SurvivalJ
Adverse Events: dasatinib vs. imatinibJ
Reasons for Discontinuation J

Dasatinib Imatinib

Overall 28% 82%

Treatment 5% 61%
Failure
Intolerance 16% 18%
 Dasatinib Conclusions
• Dasatinib targets known sources of imatinib
resistance
• Dasatinib is more effective than high dose
imatinib for CP CMP imatinib treatment failures
• Dasatinib can induce major or complete
cytogenetic responses that could yield good
long-term prognoses
• Dasatinib is gererally well tolerated but pleural
effusions are a specific side effect
Gastrointestinal Stromal (GIST) TumorsN

•4500 to 6000 new cases in US per year

•May be found incidentally or present with
abdominal pain, GI bleeding or mass
•Mesenchymal GI tumor – primarily
stomach, small intestine
•Surgical resection treatment of choice
•Median survival if not fully resected 10-23
months without adjuvant treatment
Up to Date 2007N
GIST Tumors Have Variable Clinical Courses N
• 50% Completely resected tumors recur within 5 years
• Predictors of recurrence include size, mitotic count, gastric vs non-
gastric site, radiographic appearance and KIT mutations status

Size Mitotic count

Very low risk < 2 cm < 5 per 50 HPF
Low risk 2-5 cm < 5 per 50 HPF
Intermediate risk < 5 cm 6-10 per 50 HPF
5-10 cm < 5 per 50 HPF
High risk > 5 cm > 5 per 50 HPF
> 10 cm Any mitotic rate
Any size >10 per 50 HPF

• < 5% of low and very low risk tumors recur

 Unresectable/Metastatic GIST
• Invariably fatal before 2000O
• Median survival 20 monthsL
• In local recurrence, survival 9-12 months
• <5% Response to doxorubicinL
 c-kit and GIST TumorsL,N,O,P
•Nearly all CD117 positive
•CD117 is part of c-kit receptor membrane tyrosine kinase
•95%of GIST tumors c-kit positive
•80% have activating TK mutations
•Kit activation common even without mutation
•PDGFRA mutations, some responsive
•Activating mutations of KIT and PDGFRA drive malignant
phenotype in most cases
•Imatinib inhibits KIT kinase
G.D. Demetri et al., Efficacy and safety of imatinib
mesylate in advanced gastrointestinal stromal tumors,
N Engl J Med 347 (2002), pp. 472–480.
• Open label randomized clinical trial
• 147 patients with histologically
confirmed, unresectable or metastatic
CD117+ GIST
• 400 or 600 mg imatinib daily
• No placebo control
• Vast majority had recurrent tumors
• Response based on CT/MRI
Patient Characteristics
 Response to Imatinib

Response based on tumor diameter

Median follow-up 288 days

Metabolic activity may be a better marker than tumor diameter

Overall Survival and Time to Treatment Failure L

9-12 mos
expected
survival
after
recurrence
without tx

Response defined as stable disease/CR/PR

Median duration of response not reached
Median time to response 13 weeks
Median followup after response 24 weeks
Survival Compared to Chemotherapy –
A Later StudyR
 PET responseL
•PET response seen
as early as 24 hrs
after first dose of
imatinib.

•Increases in activity
correlated with
progression

•Normal physiologic
uptake in heart, liver,
bowel, urinary system

•Cuts through center of

tumor at each time point

baseline 1 month 16 months

 Month 4 Performance StatusL
• ECOG 0 increased from 42% to 64%
• ECOG 2 or 3 decreased from 19% to 5%

Eastern cooperative oncology group (ECOG) performance scaleQ

Performance
status Definition
0 Fully active; no performance restrictions

1 Strenuous physical activity restricted; fully ambulatory and

able to carry out light work
2 Capable of all self care but unable to carry out any work
activities. Up an about > 50 percent of waking hours
3 Capable of only limited self care; confined to bed or chair
> 50 percent of waking hours
4 Completely disabled; cannot carry out any self care;
totally confined to bed or chair
 Adverse Events L

ECOG Common Toxicity Criteria: Grade 1 mild, Grade 2 moderate, Grade 3 Severe, Grade 4 Very Severe
 Adverse Events L

Myelotoxicity less common than in CML patients

Imatinib in GIST -- Conclusions
• Surgery is the first line treatment for
resectable tumors
• Imatinib targets KIT kinase, a driving force
in GIST tumors
• Imatinib substantially delays mortality and
progression compared to previous clinical
data
• Imatinib is generally well tolerated but can
lead to tumor hemorrhage
 Sunitinib (Sutent) in GIST – RationaleP,R
• 5% develop primary resistance with imatinib
• 14% develop early resistance
• Median time to acquired imatinib resistance
is 2 years
 Sunitinib (Sutent) in GIST – RationaleP
• Similarities between imatinib, sunitinib
– Bind to KIT ATP binding domain
– Sunitinib blocks KIT, PDGFRs
• Differences
– Chemical class, binding properties, affinities
• Sunitinib targets imatinib-resistant KIT mutations
– Sunitinib targets VEGFR1-3
• May inhibit tumor angiogenesis
Demetri et al. Efficacy and safety of sunitinib in patients with advanced
gastrointestinal stromal tumour after failure of imatinib: a randomised controlled
trial. Lancet. 2006. 368(9544):1329-1338.
Patient characteristics
Demetri et al. Patient Characteristics – continued
 Demitri et al Study Profile P

Trial unblinded 14 months after first randomization after initial interim data review.
Best Response to Sunitinib P

Sunitinib Placebo

CR 0 0

PR 7% (14)* 0%

Stable 58% (120) 48% (50)

Disease
Progression 19% (39) 37% (39)

*Median time to tumor response 10.4 weeks.

Time to Tumor Progression P

ITT – placebo group includes cross-overs

TTTP in high dose imatinib 11.6 weeks
Time to Tumor Progression by Baseline Characteristics R

Cox proportional hazards analysis.

Overall Survival (ITT, Weeks) P

Figure 4. Kaplan-Meier estimates of overall survival

ITT – placebo group includes cross-overs

Most Common Adverse EffectsP
 Most Common Adverse EffectsP

Most side effects managed by dose reduction

Hypothyroidism due to destructive thyroiditis shown to occur at a median of 50
weeksO
 Mutation Status May Predict BenefitO
Imatinib Sunitinib*
Response Median PFS Response Median PFS
Mutation

KIT Exon 11 84% 23 Months 5% 5 months

KIT Exon 9 48% 7 Months 37% 32 months

No mutation 0% 3 Months

*In patients who failed imatinib

Sunitinib in GIST -- Conclusions
• Patients with metastatic GIST tumors will
eventually fail imatinib
• Sunitinib may bind to resistant GIST tumor
cells due to distinct chemical properties
• Sunitinib has anti-VEGF activity which
may inhibit tumor angiogenesis
• Sunitinib prolongs survival and time to
tumor progression in imatinib resistant
GIST tumors
 Conclusions
• Rational drug design – imatinib, dasatinib, and sunitinib
are designed to target molecular abnormalities leading to
malignant phenotypes.
• Potential for improvement – knowledge of cancer
phenotypes and resistant mechanisms lead to new agents.
• Potential for patient-specific treatment – known variants
may have predictable drug responses.
• Efficacy – Tyrosine kinase inhibitors have become the first-
line standard of care in chronic phase CML and in
metastatic GIST tumors.
• Safety -- imatinib, dasatinib, and sunitinib are generally
well tolerated.
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 References
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Gauging GIST Tumor Response O

• RECIST (Response Evaluation Criteria in Solid

Tumors)
– PR 30% decrease longest dimension
– Stable disease 10% decrease to 20% increase
– 48% in later imatinib trial have good response
• Choi Criteria
– 15% reduced density CT with contrast
– Correlates with PET, gold standard
– 84% in later imatinib trial have good response
– Good imatinib response by Choi criteria
correlates better with survival