asco 2010, abstract # lba6500

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


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


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


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


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


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


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



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)



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


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



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(%)


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



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


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



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


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


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



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


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


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



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


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


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


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



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

asco 2010, abstract # lba6500

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