1 ASCO 2010, Abstract # LBA6500 Patients with Newly Diagnosed Chronic Myelogenous Leukemia in Chronic Phase (CML-CP): Twelve- month Efficacy and Safety from the Phase 3 DASISION Study Hagop Kantarjian, 1* Neil Shah, 2* Andreas Hochhaus, 3 Jorge Cortes, 1 Sandip Shah, 4 Manuel Ayala, 5 Beatriz Moiraghi, 6 M. Brigid Bradley- Garelik, 7 Chao Zhu 7 and Michele Baccarani 8 *HK and NS contributed equally and are first coauthors 1 University of Texas M.D. Anderson Cancer Center, Houston, TX; 2 Division of Hematology and Oncology, University of California San Francisco School of Medicine, San Francisco, CA; 3 Department of Hematology and Oncology, Universitätsklinikum Jena, Jena, Germany; 4 Hemato- Oncology Clinic Vedanta, Ahmedabad, India; 5 Hospital de Especialidades CMN “La Raza” Instituto Mexicano del Seguro Social, Mexico City, Mexico; 6 Hospital General De Agudos J.M. Ramos Mejia, Buenos Aires, Argentina; 7 Bristol-Myers Squibb, Wallingford, CT; 8 Department of Hematology- Oncology "L. and A. Seràgnoli", University of Bologna, Bologna, Italy ASCO 2010, Abstract # LBA6500
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1 ASCO 2010, Abstract # LBA6500 Dasatinib Compared to Imatinib in Patients with Newly Diagnosed Chronic Myelogenous Leukemia in Chronic Phase (CML-CP):
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1 ASCO 2010, Abstract # LBA6500
Dasatinib Compared to Imatinib in Patients with Newly Diagnosed Chronic Myelogenous
Leukemia in Chronic Phase (CML-CP): Twelve-month Efficacy and Safety from the
Phase 3 DASISION Study
Hagop Kantarjian,1* Neil Shah,2* Andreas Hochhaus,3 Jorge Cortes,1 Sandip Shah,4 Manuel Ayala,5
Beatriz Moiraghi,6 M. Brigid Bradley-Garelik,7 Chao Zhu7 and Michele Baccarani8
*HK and NS contributed equally and are first coauthors
1University of Texas M.D. Anderson Cancer Center, Houston, TX; 2Division of Hematology and Oncology, University of California San Francisco School of Medicine, San Francisco, CA;
3Department of Hematology and Oncology, Universitätsklinikum Jena, Jena, Germany; 4Hemato-Oncology Clinic Vedanta, Ahmedabad, India; 5Hospital de Especialidades CMN “La Raza”
Instituto Mexicano del Seguro Social, Mexico City, Mexico; 6Hospital General De Agudos J.M. Ramos Mejia, Buenos Aires, Argentina; 7Bristol-Myers Squibb, Wallingford, CT; 8Department of
Hematology-Oncology "L. and A. Seràgnoli", University of Bologna, Bologna, Italy
ASCO 2010, Abstract # LBA6500
2 ASCO 2010, Abstract # LBA6500
DisclosuresHagop Kantarjian, MD
Research Support/P.I. BMS, Novartis, Wyeth
Employee No disclosures
Consultant Novartis
Major Stockholder No disclosures
Speakers’ Bureau No disclosures
Scientific Advisory Board No disclosures
3 ASCO 2010, Abstract # LBA6500
DASISION: First-Line Dasatinib vs. Imatinib in CML-CP. Rationale
● Once daily dasatinib induces high rates of complete cytogenetic response (CCyR) and progression-free survival (PFS) in CML post imatinib failure1
● Achieving CCyR and major molecular response (MMR) by 12 mos on first-line imatinib associated with superior long-term PFS, and decreased risk of progression or death2-5
● In a single-arm phase 2 study, first-line dasatinib therapy in CML-CP resulted in high rates of CCyR and MMR6
Dasatinib Versus Imatinib Study In Treatment-naïve CML: DASISION (CA180-056). Design
● Primary endpoint: Confirmed CCyR by 12 months
● Secondary/other endpoints: Rates of CCyR and MMR; times to confirmed CCyR, CCyR and MMR; time in confirmed CCyR and CCyR; PFS; overall survival
Follow-up
5 yearsRandomized*
Imatinib 400 mg QD (n=260)
Dasatinib 100 mg QD (n=259)• N=519
• 108 centers
• 26 countries
*Stratified by Hasford risk score
5 ASCO 2010, Abstract # LBA6500
DASISION: First-Line Dasatinib vs. Imatinib in CML-CP. Endpoint Definitions
● CCyR = No Ph+ metaphases in bone marrow
● Confirmed CCyR = CCyR detected in 2 consecutive assessments (Confirmed CCyR by 12 mos* primary endpoint)
● MMR = BCR-ABL ≤0.1% (international scale)
● Unavailable sample = no response; FISH not used for response evaluation; atypical transcripts at baseline = no response
*Second confirmation could have occurred after 12 months
6 ASCO 2010, Abstract # LBA6500
DASISION: First-Line Dasatinib vs. Imatinib in CML-CP. Statistical Considerations
● Primary endpoint (confirmed CCyR by 12 mos): tested at significance level of 0.05
● Key secondary endpoints (rate of and time to MMR at any time): tested at significance level of 0.0001
● Other endpoints (rates of CCyR and MMR by 12 mos): associated P-values were descriptive, and not adjusted for multiplicity
● All analyses were performed on Intention-To-Treat (ITT) basis
7 ASCO 2010, Abstract # LBA6500
DASISION: First-Line Dasatinib vs. Imatinib
in CML-CP. Eligibility Criteria● Ph+ CML-CP within 3 mos from Dx
● No prior Rx for CML other than hydroxyurea or anagrelide
● Age ≥18 years
● ECOG performance 0–2
● Adequate organ function, including hepatic and renal function
8 ASCO 2010, Abstract # LBA6500
DASISION: First-Line Dasatinib vs. Imatinib
in CML-CP. Baseline CharacteristicsDasatinib(n=259)
Imatinib (n=260)
Median age (range), yrs 46 (18–84) 48 (18–78)
Median time since Dx, mos 1.0 1.0
Hasford risk, n (%)
Low
Intermediate
High
86 (33)
124 (48)
49 (19)
87 (33)
123 (47)
50 (19)
Prior Rx, n (%)
Hydroxyurea
Anagrelide
189 (73)
8 (3)
190 (73)
3 (1)
9 ASCO 2010, Abstract # LBA6500
DASISION: First-Line Dasatinib vs. Imatinib
in CML-CP. Dose DeliveryDasatinib
(n=258)Imatinib (n=258)
Median Rx duration, mos 14 14
Median dose intensity, mg/day 99 400
Dose escalation, n (%) 14 (5) 36 (14)
• Minimum follow-up 12 mos
• Dose escalation to dasatinib 140 mg QD and to imatinib 600–800 mg QD permitted for suboptimal response
10 ASCO 2010, Abstract # LBA6500
DASISION: First-Line Dasatinib vs. Imatinib in CML-CP. CCyR Rate by 12 Mos (ITT)
8377
7266
0
20
40
60
80
100
Dasatinib100 mg QD
Imatinib400 mg QDCCyR
(%)
Confirmed CCyRby 12 months
CCyRby 12 months
P=0.0011P=0.0067
11 ASCO 2010, Abstract # LBA6500
DASISION: First-Line Dasatinib vs. Imatinib
in CML-CP. CCyR rates (ITT)
• By analysis of time to CCyR, likelihood of achieving CCyR at any time ~50% higher with dasatinib than with imatinib (stratified log-rank P<0.0001; HR=1.53)
54
7378
83
31
5967
72
0
20
40
60
80
100
Mo 3 Mo 6 Mo 9 Mo 12
P=0.0011Dasatinib 100mg QD Imatinib 400mg QD
CCyR(%)
12 ASCO 2010, Abstract # LBA6500
DASISION: First-Line Dasatinib vs. Imatinib in CML-CP. MMR Rates (ITT)
8
27
3946
52
0.48
18
2834
0
20
40
60
80
100Dasatinib 100 mg QD
Imatinib 400 mg QD
P<0.0001
MMR(%)
Mo 3 Mo 6 Mo 9 Mo 12 Any time
P<0.00003
13 ASCO 2010, Abstract # LBA6500
DASISION: First-Line Dasatinib vs. Imatinib
in CML-CP. Time to MMR
• Patients were twice as likely to achieve MMR at any time with dasatinib vs. imatinib
• In patients achieving MMR, median time to MMR 6.3 mos with dasatinib vs. 9.2 mos with imatinib
MMR(%)
Mos0 3 6 9 12 15 18 21 24 27
100
80
60
40
20
0
P<0.0001 (stratified log-rank)
Hazard ratio for dasatinib over imatinib: 2.01
Dasatinib
Imatinib
14 ASCO 2010, Abstract # LBA6500
DASISION: First-Line Dasatinib vs. Imatinib in CML-CP. 12-mos MMR Rates by Hasford Risk
56
45
3136
28
16
0
20
40
60
80
100
Low Intermediate High
MMR(%)
Dasatinib 100mg QD Imatinib 400mg QD
15 ASCO 2010, Abstract # LBA6500
DASISION: First-Line Dasatinib vs. Imatinib
in CML-CP. Progression to AP/BP
● No patient who achieved MMR progressed to accelerated or blast phase
● 2 patients who achieved CCyR progressed to accelerated or blast phase (1 with dasatinib, 1 with imatinib)