Georges CHAHINE, MD

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Best of ASCO 2008Mzaar, Lebanon

• Georges CHAHINE, MD

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Dasatinib 2-year efficacy in patientswith
chronic-phase chronic myelogenous leukemia
(CML-CP) with resistance or intolerance to
imatinib (START-C)

• Michael Mauro,1,2 Michele Baccarani,2Francisco
  Cervantes,2 Jeffrey Lipton,2 Yousif
  Matloub,3Ritwik Sinha,3 Richard Stone2
• 1Oregon Health and Science University, Portland,
  OR, USA
• 2START-C Trial Study Group3Bristol-Myers Squibb
  Co., Wallingford, CT, USA

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Background
Dasatinib 70 mg BID in chronic-phase CML

• Imatinib resistance and intolerance in
  chronic-phase CML are of increasing clinical
  relevance
• 31 of IRIS patients discontinued imatinib in 5
  years1
• more than half (18) due to resistance or
  intolerance
• the remainder (13) for other reasons
• Dasatinib is the most potent BCR-ABL inhibitor
• 325-fold more potent than imatinib and 16-fold
  more potent than nilotinib in vitro2
• START-C Phase II study of 387 patients with
  chronic-phase CML resistant or intolerant to
  imatinib treated with dasatinib 70 mg BID
• follow-up 24 months (2 years of data available
  since last enrolled patient)

1Druker et al. N Engl J Med 2006355240817
2OHare et al. Cancer Res 20056545005
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Baseline disease characteristics
Dasatinib 70 mg BID in chronic-phase CML
Baseline mutation data were available for 369
patients
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Rate and durability of MCyR with dasatinib
Dasatinib 70 mg BID in chronic-phase CML
100 80 60 40 20 0
without loss of MCyR
0 3 6 9 12 15 18 21 24 27 30
Months
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Rate and durability of CCyR with dasatinib
Dasatinib 70 mg BID in chronic-phase CML
100 80 60 40 20 0
without loss of CCyR
0 3 6 9 12 15 18 21 24 27 30
Months
MMR evaluated among those patients with CCyR MMR
definition 0.1 BCR-ABL/control by RQ-PCR
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Response to dasatinib by baseline status
Dasatinib 70 mg BID in chronic-phase CML
Overall
Achieved new response
100
91
87
80
62
59
60
53
52
Percent
40
20
0
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PFS and overall survival with dasatinib
Dasatinib 70 mg BID in chronic-phase CML
100 80 60 40 20 0
Percent
0 3 6 9 12 15 18 21 24 27 30 33
Months
Progression was defined as increasing WBC count,
loss of CHR / MCyR, confirmed AP / BP, or death
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Imatinib resistant patientsRate and durability
of MCyR to dasatinib
Dasatinib 70 mg BID in chronic-phase CML
100 80 60 40 20 0
without loss of MCyR
0 3 6 9 12 15 18 21 24 27 30
Months
15
Imatinib resistant patientsRate and durability
of CCyR to dasatinib
Dasatinib 70 mg BID in chronic-phase CML
100 80 60 40 20 0
without loss of CCyR
0 3 6 9 12 15 18 21 24 27 30
Months
MMR evaluated among those patients with CCyR MMR
definition 0.1 BCR-ABL / control by RQ-PCR
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Imatinib resistant patientsPFS and overall
survival with dasatinib
Dasatinib 70 mg BID in chronic-phase CML
100 80 60 40 20 0
Percent
0 3 6 9 12 15 18 21 24 27 30 33
Months
Progression was defined as increasing WBC count,
loss of CHR / MCyR, confirmed AP / BP, or death
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Durability of CCyR on dasatinib based on prior
cytogenetic response imatinib resistant patients
Dasatinib 70 mg BID in chronic-phase CML
100 80 60 40 20 0
without loss of CCyR
Patients without loss of CCyR
n
12 months
24 months
0 3 6 9 12 15 18 21 24 27 30
Months
No prior CyR no CyR of any level achieved
during prior imatinib treatment
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Dasatinib 70 mg BID in chronic-phase CML
Response by individual baseline BCR-ABL mutation
Cellular IC50 (nM)
n
Imatinib
Dasatinib
17
2000
1.3
M244V
9
1500
L248V
23
13503900
1.8
G250E/V
14
gt10000
1.310
Y253F/H/K
10
44008400
5.613
E255K/V
3
1500
D276G
Complete CyRPartial CyR Complete HR No response
3
gt10000
gt1000
T315I
4
1050
7.4
F317L
15
930
1.1
M351T
6
400
E355G
8
1200
2.2
F359C/I/V
2
1000
2.0
L387M
17
8504200
0.61.13
H396P/R
30
Other
P-loop residues 248-256 are highlighted
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Dasatinib efficacy by baseline BCR-ABL mutation
Dasatinib 70 mg BID in chronic-phase CML
100 80 60 40 20 0
not progressed
0 3 6 9 12 15 18 21 24 27 30 33
Months
43 different BCR-ABL mutations were observed at
baseline
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Grade 3/4 cytopenias
Dasatinib 70 mg BID in chronic-phase CML
100 80 60 40 20 0
Follow-up (N387)
12 months
48
Percent
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Leukopenia Neutropenia Thrombocytopenia
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Non-hematologic side-effects
Dasatinib 70 mg BID in chronic-phase CML
Diarrhea Rash Dyspnea Fatigue Headache Superficial
edema Pleural effusion Nausea
N387
Grade 1/2
12 Months
Grade 3/4
12 Months
No pleural effusionswere grade 4
0
20
40
60
80
100
Patients ()
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Lack of dasatinib cross-intolerance to
imatinibRecurrence during dasatinib treatment of
toxicity that caused imatinib intolerance
Dasatinib 70 mg BID in chronic-phase CML
All 3 dasatinib patients were able to continue
treatment after dose reduction
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Imatinib intolerant patientsRate and durability
of MCyR to dasatinib
Dasatinib 70 mg BID in chronic-phase CML
100 80 60 40 20 0
without loss of MCyR
0 3 6 9 12 15 18 21 24 27 30
Months
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Imatinib intolerant patientsRate and durability
of CCyR to dasatinib
Dasatinib 70 mg BID in chronic-phase CML
100 80 60 40 20 0
without loss of CCyR
0 3 6 9 12 15 18 21 24 27 30
Months
MMR evaluated among those patients with CCyR MMR
definition 0.1 BCR-ABL / control by RQ-PCR
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Imatinib intolerant patientsPFS and overall
survival with dasatinib
Dasatinib 70 mg BID in chronic-phase CML
100 80 60 40 20 0
Percent
0 3 6 9 12 15 18 21 24 27 30 33
Months
Progression was defined as increasing WBC count,
loss of CHR / MCyR, confirmed AP / BP, or death
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Conclusions
Dasatinib 70 mg BID in chronic-phase CML

• 2-year data (N387) demonstrate continuing
  efficacyof dasatinib
• overall MCyR 62, CCyR 53, MMR among CCyR 79
• 88 continue in MCyR, 90 in CCyR at 2 years
• PFS 80 at 2 years
• overall survival 94 at 2 years
• Dasatinib efficacy demonstrated across subgroups,
  including
• all but one of 43 different baseline mutations
• patients with P-loop mutations or no prior CyR to
  imatinib
• Dasatinib 70 mg BID treatment was well tolerated
• lack of dasatinib cross-intolerance to imatinib

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Dasatinib dose optimization
Dasatinib 70 mg BID in chronic-phase CML

• 2-year START-C data with dasatinib 70 mg BID
  longest follow-up in chronic-phase CML
• In the subsequent phase III dose-optimization
  study (034) of chronic-phase CML1, dasatinib 100
  mg once daily arm was optimal
• similar efficacy
• less frequent fluid retention and cytopenia
• most favorable risk-benefit ratio
• approved for chronic-phase CML

1Shah et al, ASCO 2007, abstract 7004
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Participating centers
Dasatinib 70 mg BID in chronic-phase CML
Australia Andrew Grigg Tim Hughes Chris
Arthur John Seymour Kerry Taylor Austria Peter
Valent Belgium Andre Bosly Canada Jeffrey H
Lipton Donna Forrest Carlo Gambacorti-Passerin
i Pierre Laneuville Denmark Johan Lanng
Nielsen Finland Kimmo Porkka France Hervé
Dombret François Guilhot Josy
Reiffers Philippe Rousselot Mauricette
Michalet Thierry Facon Frédéric
Maloisel Jean-Luc Harrousseau Germany Andreas
Hochhaus Carsten Bokemeyer Thomas
Fischer Ute Berger Michael Schatz Dietger
Niederwieser Ireland Eibhlin Conneally Michael
ODwyer
Israel Aron Nagler Italy Michele
Baccarani Sergio Amadori Giuseppe
Saglio Giorgio Lambertenghi Vincenzo
Liso Bruno Rotoli Felicetto
Ferrara Korea Dong-Wook Kim The Netherlands Jan
Cornelissen AVMB Schattenberg Peru Juan
Navarro Singapore Yeow Tee Goh Spain Francisco
Cervantes Jesus Odriozola Juan Luis
Steegmann Sweden Bengt Simonsson Leif
Stenke Marja Ekblom Berit Markevarn Switzerla
nd Alois Gratwohl UK Jane Apperley Tessa
Holyoake USA Moshe Talpaz Neil P Shah Kapil
Bhalla Steven Coutre John Dipersio Brian
Druker
USA Hagop Kantarjian H Jean Khoury Charles
Schiffer Richard T Silver Richard M
Stone Aaron Rapoport Richard Larson F
Anthony Greco Syed Bilgrami Stuart
Goldberg Bruce Cheson Robert Collins John
Lister Michael Lilly Roger Strair Selina
Luger Candido E Rivera Louis
Fehrenbacher Ajit Maniam Magaral S
Murali Jeffrey K Giguere Joseph
McGuirk Molecular Susan Branford,
Australiabiology Jerry Radich, USA Martin
Müller, Germany Philipp Erben, Germany