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
1. Shah. Haematologica. 2010;95:2322. Druker. NEJM. 2006;355:24083. Druker. ASCO 2006, abst 6506
4. de Lavallade. JCO. 2008;26:33585. Cortes. JCO. 2010;28:4246. Cortes. JCO. 2010;28:398
4 ASCO 2010, Abstract # LBA6500
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)
5
9
0
5
10
15
Progressedto AP/BP
(n)
3.5%
1.9%
Dasatinib 100 mg QD
Imatinib 400 mg QD
16 ASCO 2010, Abstract # LBA6500
Patients at riskDasatinib 259 254 253 248 208 124 73 29 4 0Imatinib 260 257 254 250 222 126 77 36 8 0
0 3 6 9 12 15 18 21 24 27
100
80
60
40
20
0
Survival(%)
Mos
Deaths/Randomized (n) 12-mo OS (KM)
Dasatinib 10/259 97.2%
Imatinib 6/260 98.8%
DASISION: First-Line Dasatinib vs. Imatinib in CML-CP. Overall Survival
17 ASCO 2010, Abstract # LBA6500
DASISION: First-Line Dasatinib vs. Imatinib in CML-CP. Treatment Discontinuations
*Includes consent withdrawal, pregnancy, lost to follow-up and death
% Patients
Dasatinib 100 mg QDn=258
Imatinib 400 mg QDn=258
Still on treatment 84.5 81.4
Discontinued 15.5 18.6
Treatment failure including progression
5.0 8.9
Study drug toxicity 5.0 4.3
Adverse event unrelated 1.2 0.4
Other reason* 4.2 5.0
18 ASCO 2010, Abstract # LBA6500
DASISION: First-Line Dasatinib vs. Imatinib
in CML-CP. Grade 3/4 Cytopenias
● Grade 3/4 bleeding: 1 patient on dasatinib and 2 patients on imatinib
● 4 patients on dasatinib and 3 on imatinib D/C Rx due to cytopenia
● 75% of cytopenias in both arms occurred during the first 4 mos of Rx
Patients(%)
10
21 19
7
2010
0
20
40
60
80
100Dasatinib 100mg QD Imatinib 400mg QD
Anemia Neutropenia Thrombocytopenia
19 ASCO 2010, Abstract # LBA6500
DASISION: First-Line Dasatinib vs. Imatinib inCML-CP. Drug-Related Nonhematologic AEs (10%)
% Patients
Dasatinib Imatinib
All grades Grade 3/4 All grades Grade 3/4
Nausea 8 0 20 0
Vomiting 5 0 10 0
Rash 11 0 17 1
Muscle inflammation 4 0 17 0
Myalgia 6 0 12 0
Musculoskeletal pain 11 0 14 <1
Diarrhea 17 <1 17 1
Fatigue 8 <1 10 0
Headache 12 0 10 0
Fluid retention 19 1 42 1
Superficial edema 9 0 36 <1
Pleural effusion 10 0 0 0
20 ASCO 2010, Abstract # LBA6500
DASISION: First-Line Dasatinib vs. Imatinib in CML-CP. Forest Plots Comparing Differences in AE Rates
*Myalgia = myalgia, muscle inflammation and MSK pains
–0.4 –0.2 0 0.2 0.4
Rate difference (dasatinib–imatinib) with exact 95% CI
Headache
Superficial edemaFluid retention
FatigueDiarrheaRashVomitingNauseaMyalgia*Thrombocytopenia, grade 3/4Neutropenia, grade 3/4Anemia, grade 3/4
Pleural effusion
Favors dasatinib Favors imatinib
21 ASCO 2010, Abstract # LBA6500
DASISION: First-Line Dasatinib vs. Imatinib
in CML-CP. Pleural Effusions on DasatinibPleural effusion, n (%)
Grade 1 5 (2)
Grade 2 21 (8)
Grade 3 or above 0
Pleural effusion management (n=26)
Dasatinib dose interruption 19
Diuretics 12
Dasatinib dose reduction 8
Corticosteroids 7
Therapeutic thoracentesis 1
● 1.2% (3 patients) stopped dasatinib due to pleural effusion
• 24/26 patients (92%) with pleural effusion achieved CCyR by 12 mos
22 ASCO 2010, Abstract # LBA6500
DASISION: First-Line Dasatinib vs. Imatinib in CML-CP. Grade 3/4 Lab Abnormalities
● 4 patients on imatinib and none on dasatinib D/C Rx due to lab abnormality
% Patients
Dasatinib Imatinib
Phosphorus ↓ 4 21
ALT ↑ <1 1
AST ↑ <1 1
Total bilirubin ↑ 1 0
Alkaline phosphatase ↑ <1 0
Lipase ↑ 0 0
Amylase ↑ 0 0
Glucose ↑ 0 0
23 ASCO 2010, Abstract # LBA6500
DASISION: First-Line Dasatinib vs. Imatinib in CML-CP. Effect of Treatment on QTcF
Dasatinib Imatinib
Median change from baseline, msec 3.0 8.2
Absolute QTcF 450–500 msec, % 2 4
Absolute QTcF >500 msec, % 0.4 0.4
QTcF increase 30–60 msec, % 6 11
QTcF increase >60 msec, % 5 5
24 ASCO 2010, Abstract # LBA6500
DASISION: First-Line Dasatinib vs. Imatinib in CML-CP. Conclusions● Superior efficacy of dasatinib vs. imatinib in first-line Rx of CML-CP
– Higher/faster rates of CCyR, confirmed CCyR, MMR
– Advantage across Hasford risk groups
● Low rate of progression (dasatinib 1.9% vs imatinib 3.5%)
● Dasatinib well tolerated
– Low rates of grade 3/4 cytopenia, nonheme AEs, and lab abns.
– No grade 3/4 pleural effusions
– Few D/C due to toxicity
● Based on predictive value of CCyR, longer FU of first-line dasatinib may demonstrate better long-term outcomes than imatinib
● Dasatinib 100 mg once daily should become frontline Rx in newly Dx CML-CP
25 ASCO 2010, Abstract # LBA6500
DASISION: First-Line Dasatinib vs. Imatinib
in CML-CP. Investigators
Study Steering/Authoring Committee: M Baccarani, J Cortes, A Hochhaus, H Kantarjian, N Shah
ChinaJ HuX HuangZ ShenJ WangColumbiaL EncisoC RamirezCzech RepublicE FaberH KlamovaJ MayerJ VoglovaDenmarkJ StentoftFranceC BerthouD BordessouleA BuzynV DubruilleM Escoffre-BarbeT FaconA Guerci-BreslerF GuilhotR HerbrechtF HuguetM MichalletD ReaJF Rossi
PolandJ HolowieckiM KomarnickiT RobakA SkotnickiK WarzochaRussiaN KhoroshkoY ShatokhinA ZaritskySingaporeCTH ChuahSouth KoreaDW KimKH LeeSpainA AlvarezC BoqueC Del CanizoF CervantesA Jimenez-VelascoJ Martinez-DominguezA Ramirez PayerR De PazM PerezJL SteegmannTurkeyM CetinI Haznedaroglu
ArgentinaE BullorskyJ MiloneB MoiraghiS PavlovskyAustraliaS DurrantR HerrmannA NicolP RowlingsAustriaG GastlP ValentBelgiumJ Van DroogenbroeckA FerrantBrazilAM CoelhoV ColturatoPE Dorlhiac LlacerR PasquiniC De SouzaMA ZanichelliChileM Soledad Undurraga
GermanyP le CoutreC JunghanssM SoeklerF StegelmannGreeceA FassasHungaryS FeketeM UdvardyIndiaU AgarwalVP GangadharanV MathewG NarayanK PrabhashT SaikiaS ShahItalyE AbruzzeseG AlimenaC Gambacorti-PasseriniM LazzarinoF Di RaimondoG Saglio
JapanH AkiyamaS FujisawaM HinoY IshidaK IshizawaK MatsueH NakamaeM OguraK TamuraM TanimotoM TaniwakiK UsukiA UtsunomiyaMexicoD Gomez AlmaguerJL AyalaA GonzalezJJ Kassack IpiñaR Rivas LlamasNetherlandsAVMB SchattenbergE VellengaPeruL CasanovaJ NavarroJM Zenteno