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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

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ASCO 2010, Abstract # LBA6500

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  1. 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,5Beatriz 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. DisclosuresHagop Kantarjian, MD

  3. 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 4. de Lavallade. JCO. 2008;26:3358 5. Cortes. JCO. 2010;28:424 6. Cortes. JCO. 2010;28:398 1. Shah. Haematologica. 2010;95:232 2. Druker. NEJM. 2006;355:2408 3. Druker. ASCO 2006, abst 6506

  4. 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 Dasatinib 100 mg QD (n=259) Imatinib 400 mg QD (n=260) • N=519 • 108 centers • 26 countries Follow-up 5 years Randomized* *Stratified by Hasford risk score

  5. 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. DASISION: First-Line Dasatinib vs. Imatinib in CML-CP. StatisticalConsiderations • 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. 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. DASISION: First-Line Dasatinib vs. Imatinib in CML-CP. Baseline Characteristics

  9. DASISION: First-Line Dasatinib vs. Imatinib in CML-CP. Dose Delivery • Minimum follow-up 12 mos • Dose escalation to dasatinib 140 mg QD and to imatinib 600–800 mg QD permitted for suboptimal response

  10. DASISION: First-Line Dasatinib vs. Imatinib in CML-CP. CCyR Rate by 12 Mos (ITT) P=0.0011 P=0.0067 CCyR (%) CCyRby 12 months Confirmed CCyRby 12 months

  11. 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) Dasatinib 100mg QD Imatinib 400mg QD P=0.0011 CCyR (%) Mo 3 Mo 6 Mo 9 Mo 12

  12. DASISION: First-Line Dasatinib vs. Imatinib in CML-CP. MMR Rates (ITT) P<0.00003 P<0.0001 MMR (%) Mo 3 Mo 6 Mo 9 Mo 12 Any time

  13. DASISION: First-Line Dasatinib vs. Imatinib in CML-CP. Time to MMR 100 80 60 40 20 0 P<0.0001 (stratified log-rank) Hazard ratio for dasatinib over imatinib: 2.01 MMR (%) Dasatinib Imatinib 0 3 6 9 12 15 18 21 24 27 Mos • 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

  14. DASISION: First-Line Dasatinib vs. Imatinib in CML-CP. 12-mos MMR Rates by Hasford Risk Dasatinib 100mg QD Imatinib 400mg QD MMR (%)

  15. 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) Dasatinib 100 mg QD Imatinib 400 mg QD Progressed to AP/BP (n) 3.5% 1.9%

  16. DASISION: First-Line Dasatinib vs. Imatinib in CML-CP. Overall Survival 100 80 60 40 20 0 Survival(%) 0 3 6 9 12 15 18 21 24 27 Mos Patients at risk Dasatinib 259 254 253 248 208 124 73 29 4 0 Imatinib 260 257 254 250 222 126 77 36 8 0

  17. DASISION: First-Line Dasatinib vs. Imatinib in CML-CP. Treatment Discontinuations *Includes consent withdrawal, pregnancy, lost to follow-up and death

  18. Dasatinib 100mg QD Imatinib 400mg QD 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 (%) Anemia Neutropenia Thrombocytopenia

  19. DASISION: First-Line Dasatinib vs. Imatinib inCML-CP. Drug-Related Nonhematologic AEs (10%)

  20. DASISION: First-Line Dasatinib vs. Imatinib in CML-CP. Forest Plots Comparing Differences in AE Rates Anemia, grade 3/4 Neutropenia, grade 3/4 Thrombocytopenia, grade 3/4 Myalgia* Nausea Vomiting Rash Diarrhea Fatigue Headache Fluid retention Superficial edema Pleural effusion –0.4 –0.2 0 0.2 0.4 Rate difference (dasatinib–imatinib) with exact 95% CI *Myalgia = myalgia, muscle inflammation and MSK pains Favors dasatinib Favors imatinib

  21. DASISION: First-Line Dasatinib vs. Imatinib in CML-CP. Pleural Effusions on Dasatinib • 24/26 patients (92%) with pleural effusion achieved CCyR by 12 mos • 1.2% (3 patients) stopped dasatinib due to pleural effusion

  22. 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

  23. DASISION: First-Line Dasatinib vs. Imatinib in CML-CP. Effect of Treatment on QTcF

  24. 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. DASISION: First-Line Dasatinib vs. Imatinib in CML-CP. Investigators ArgentinaE BullorskyJ MiloneB MoiraghiS Pavlovsky AustraliaS DurrantR HerrmannA NicolP Rowlings AustriaG GastlP Valent BelgiumJ Van DroogenbroeckA Ferrant BrazilAM CoelhoV ColturatoPE Dorlhiac LlacerR PasquiniC De SouzaMA Zanichelli ChileM Soledad Undurraga ChinaJ HuX HuangZ ShenJ Wang ColumbiaL EncisoC Ramirez Czech RepublicE FaberH KlamovaJ MayerJ Voglova DenmarkJ Stentoft FranceC BerthouD BordessouleA BuzynV DubruilleM Escoffre-BarbeT FaconA Guerci-BreslerF GuilhotR HerbrechtF HuguetM MichalletD ReaJF Rossi GermanyP le CoutreC JunghanssM SoeklerF Stegelmann GreeceA Fassas HungaryS FeketeM Udvardy IndiaU AgarwalVP GangadharanV MathewG NarayanK PrabhashT SaikiaS Shah ItalyE AbruzzeseG AlimenaC Gambacorti-PasseriniM LazzarinoF Di RaimondoG Saglio JapanH AkiyamaS FujisawaM HinoY IshidaK IshizawaK MatsueH NakamaeM OguraK TamuraM TanimotoM TaniwakiK UsukiA Utsunomiya MexicoD Gomez AlmaguerJL AyalaA GonzalezJJ Kassack IpiñaR Rivas Llamas NetherlandsAVMB SchattenbergE Vellenga PeruL CasanovaJ NavarroJM Zenteno PolandJ HolowieckiM KomarnickiT RobakA SkotnickiK Warzocha RussiaN KhoroshkoY ShatokhinA Zaritsky SingaporeCTH Chuah South KoreaDW KimKH Lee SpainA AlvarezC BoqueC Del CanizoF CervantesA Jimenez-VelascoJ Martinez-DominguezA Ramirez PayerR De PazM PerezJL Steegmann TurkeyM CetinI Haznedaroglu Study Steering/Authoring Committee: M Baccarani, J Cortes, A Hochhaus, H Kantarjian, N Shah

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