DASATINIB (BMS ) FDA’s Oncologic Drugs Advisory Committee Meeting 2 June 2006

Introduction Donna Morgan Murray, PhD Bristol-Myers Squibb Global Regulatory Sciences

3 BMS Presentation Introduction.………………..Donna Morgan Murray, PhD BMS, Global Regulatory Sciences Scientific Rationale……….Neil Shah, MD, PhD UCSF School of Medicine Clinical Program……………Claude Nicaise, MD BMS, Global Development Clinical Perspective……...Hagop Kantarjian, MD MD Anderson Cancer Center Conclusion………………….Donna Morgan Murray, PhD

4 Consultants Available to the Committee Neil Shah, MD, PhD Assistant Professor Division of Hematology/Oncology Department of Medicine UCSF School of Medicine San Francisco, CA Hagop Kantarjian, MD Chairman & Professor Leukemia Department The University of Texas MD Anderson Cancer Center Houston, TX

5 Medical Need for Therapeutic Options in CML ChronicAcceleratedBlast u Chronic Myeloid Leukemia (CML) is usually treated with imatinib, although resistance and intolerance develops u After imatinib failure, therapeutic options are limited (e.g., escalated doses of imatinib, hydroxyurea, interferon, investigational agents, stem cell transplants) u Dasatinib offers a therapeutic option to patients in all phases of CML after failure with imatinib

6 Proposed Indications for Dasatinib u Treatment of adults with chronic, accelerated, or blast phase chronic myeloid leukemia (CML) with resistance or intolerance to prior therapy including imatinib u Treatment of adults with Philadelphia chromosome ‑ positive (Ph+) acute lymphoblastic leukemia (ALL) and lymphoid blast chronic myeloid leukemia with resistance or intolerance to prior therapy

Scientific Rationale Neil Shah, MD, PhD UCSF School of Medicine

8 Ph chromosome BCR-ABL activated tyrosine kinase) BCR-ABL (activated tyrosine kinase) BCRABL CML The Philadelphia (Ph) Chromosome Leads to CML

9 Loss of Response to Imatinib in CML Chronic Phase – Frontline16%(42 months) Chronic Phase – IFN failure26% Accelerated Phase73% (48 months) Blast Crisis95% Rate of Relapse/Progression Silver et al, 2004; Guilhot et al, 2004; Bhatia et al, 2002; Graham et al, 2002 For most imatinib-resistant or -intolerant patients, effective therapeutic options are severely limited

10 Clinical Resistance to Imatinib is Associated with Restoration of BCR-ABL Kinase Activity Mechanisms u u Outgrowth of one or more clones harboring an imatinib-resistant BCR-ABL kinase domain mutation (most common) u u Overproduction of BCR-ABL via genomic amplification u BCR-ABL-independent mechanisms

11 E255K/V M244V M351T Y253H/F E279K F317L E355G/D F359C/V/D/I H396R/P Q252H/R E459K/Q F486S E450G/Q M388L G250E/A/F D276G T277A L387F/M V379I A397P E453G/K T315I/N F311L/I V289A L298V L248V E281A L364I G383D E292V x Gorre et al, 2001; von Bubnoff et al, 2002; Branford et al, 2002; Hofmann et al, 2002; Roche-L’Estienne et al, 2002; Shah et al, 2002; Hochhaus et al, 2002; Al-Ali et al, 2004 P C A Courtesy Tim Hughes Map of BCR-ABL Kinase Domain Mutations Associated with Clinical Resistance to Imatinib S417Y

12 Dasatinib Inhibits Growth of 14/15 Imatinib-Resistant BCR-ABL-Expressing Ba/F3 Cell Lines in vitro Shah et al, Science, 2004 Normalized cell number 48 hours of drug exposure Concentration of dasatinib (nM)* T315I Q252H Ba/F3 Bcr-Abl E255K M351T M244V G250E Q252R Y253F Y253H E255V F317L E355G F359V H396R F486S T315I Parental Ba/F3 cells *Dasatinib is x more potent than imatinib in vitro

13 CML imatinib-sensitive (no mutation) CML imatinib-resistant (BCR-ABL/M351T) Normal vehicle 5 nM BMS Dasatinib Selectively Inhibits BCR-ABL-dependent Hematopoiesis in vitro Shah et al, Science 2004 Normal vehicle 5 nM dasatinib

14 Summary of Scientific Rationale: Dasatinib for Imatinib-resistant and -intolerant CML u Imatinib resistance –Potently inhibits nearly all imatinib-resistant BCR-ABL kinase domain mutations – x more potent than imatinib at inhibiting the activity of BCR-ABL u Imatinib intolerance –Structurally unrelated to imatinib, therefore, cross-intolerance not likely u Selectively inhibits the growth of BCR-ABL-positive hematopoietic progenitors

Clinical Program Claude Nicaise, MD Bristol-Myers Squibb Global Development

16 Clinical Program – Six Studies at 68 Centers One Phase I Study (002) u Dose escalation study –15 mg to 180 mg QD and 25 mg to 70 mg BID in chronic phase –35 mg to 120 mg BID in advanced disease u Intrapatient dose escalation / decrease to safe and effective dose Four Phase II Studies (013, 005, 006 and 015) u Open label u Patients resistant or intolerant to imatinib One Randomized Phase II Study (017) u Open label u Control group: imatinib 800 mg/day u Cross-over for lack of response or intolerance

17 Rationale for 70 mg BID Dose Selection u Optimal drug exposure –Pharmacokinetic parameters Cmax: 45 ng/mL (90 nM)Cmax: 45 ng/mL (90 nM) –Pharmacodynamics and inhibition of pCRKL ≈ 100% at doses  100 mg/day≈ 100% at doses  100 mg/day BID > QDBID > QD u Effective dose in Phase I study (002) 70 mg BID u Acceptable safety in Phase I study (002)

18 Imatinib Resistance Resistance at the maximum tolerated dose of imatinib u Primary resistance –No complete hematologic response at 3 months –No cytogenetic response at 6 months –No major cytogenetic response at 1 year u Secondary resistance –Loss of complete hematologic response –Loss of major cytogenetic response –Progression to accelerated / blast

19 Imatinib Intolerance u Imatinib toxicities leading to intolerance –Grade 3-4 non-hematologic toxicity –Grade 4 hematologic toxicity lasting more than 7 days u Patients who responded to imatinib –Developed intolerance while in response –Unable to resume therapy u Patients who never responded to imatinib –Unable to tolerate imatinib at a dose of at least 400 mg

20 Response Criteria ChronicAdvanced Hematologic Response CompleteComplete No Evidence of Leukemia WBC ≤ ULN Blasts/Promyelocytes in Peripheral Blood 000 Blasts in Bone Marrow N/A ≤ 5% Basophils < 20% Myelocytes plus Metamyelocytes in Peripheral Blood < 5% Platelets x 10 9 /L < 450 ≥ – < 100 Neutrophils x 10 9 /L N/A ≥ 1≥ 1≥ 1≥ – < 1 Extramedullary Disease NoNoNo Cytogenetic Response Complete (CCyR)Partial (PCyR)Major (MCyR) 0% Ph+1% – 35% Ph+CCyR + PCyR 0% Ph+1% – 35% Ph+CCyR + PCyR

21 Patients in Clinical Program No. of Patients in Phase I and II Total Chronic40––186–226 Accelerated11107–––118 M. Blast 23–74––97 L. Blast / ALL 10–––7888 Total Randomized Trial: Study patients (22 dasatinib and 14 imatinib)

22 Baseline Characteristics n (%) of Patients Chronic N = 226 Accelerated N = 118 M. Blast N = 97 L. Blast/ Ph+ ALL N = 88 Median Duration of CML (months) Prior Imatinib Resistance Resistance 159 (70) 106 (90) 90 (93) 80 (91) Dose >600 mg/day Dose >600 mg/day 123 (54) 70 (59) 49 (51) 46 (52) Duration >3 years Duration >3 years 122 (54) 79 (67) 44 (45) 12 (14) Prior Interferon 167 (74) 89 (75) 53 (55) 25 (28) Prior Chemotherapy 101 (45) 76 (64) 64 (66) 75 (85) Prior Stem Cell Transplant 19 (8) 19 (16) 14 (14) 34 (39) BCR-ABL Mutations 113 (50) 64 (54) 40 (41) 43 (49) Platelets <100 x 10 9 /L 16 (7) 16 (7) 47 (40) 70 (72) 65 (74)

Efficacy in Chronic Phase CML Studies 002, 013 and 017

24 Chronic Phase CML Efficacy in Imatinib-resistant Patients n (%) of Patients Study 002 N = 32 Study 013 N = 127 Hematologic Response Complete (CHR) Complete (CHR) 29 (91) 111 (87) Cytogenetic Response Major (MCyR) Major (MCyR) 12 (38) 40 (31) 40 (31) Complete (CCyR) Complete (CCyR) 9 (28) 9 (28) 28 (22) 28 (22) Loss of CHR 02 Loss of MCyR 00

25 Major Cytogenetic Response Rate in Imatinib-resistant Patients Percent Responders N = Chronic Phase CML 10/299/2530/9832/9225/6010/2712/3240/127n/N =

26 Efficacy in Imatinib-intolerant Patients n (%) of Patients Study 002 N = 8 Study 013 N = 59 Hematologic Response Complete (CHR) Complete (CHR) 8 (100) 57 (97) Cytogenetic Response Major (MCyR) Major (MCyR) 6 (75) 43 (73) Complete (CCyR) Complete (CCyR) 5 (63) 33 (56) Loss of CHR 00 Loss of MCyR 00 Chronic Phase CML

27 Major Cytogenetic Response in Imatinib-intolerant Patients Percent Responders 8N = /8n/N =6/843/5922/32 Chronic Phase CML

28 Progression-free Survival Proportion Not Progressed Months 002 Int 002 Res 013 Res 013 Int Censored Intolerant 002 Resistant 013 Intolerant 013 Resistant N Number Progressed 0308 Chronic Phase CML IntolerantResistantNProgressionNProgression Study Study

29 Preliminary Data of the Randomized Study 017 n (%) of Patients Dasatinib N = 22 Imatinib N = 14 Baseline Characteristics Prior Imatinib 600 mg/day Prior Imatinib 600 mg/day 16 (73) 12 (86) Prior Interferon Prior Interferon 14 (64) 11 (79) BCR-ABL Mutations BCR-ABL Mutations 10 (45) 1 (7) Efficacy Complete Hematologic Response Complete Hematologic Response 21 (95) 13 (93) Major Cytogenetic Response Major Cytogenetic Response 10 (45) 3 (21) Complete Cytogenetic Response Complete Cytogenetic Response 7 (32) 1 (7) Crossover 2 (9) 11 (79) Chronic Phase CML

Efficacy in Accelerated Phase CML Studies 002 and 005

31 Efficacy Results n (%) of Patients Study 002 N = 11 Study 005 N = 107 Hematologic Response Major (MaHR) Major (MaHR) 6 (55) 63 (59) Complete (CHR) Complete (CHR) 5 (45) 35 (33) No Evidence of Leukemia No Evidence of Leukemia 1 (9) 28 (26) Cytogenetic Response Major (MCyR) Major (MCyR) 3 (27) 33 (31) Complete (CCyR) Complete (CCyR) 2 (18) 23 (22) Loss of MaHR 01 Loss of MCyR 02 Accelerated Phase CML

32 Progression-free Survival N11107 Number Progressed 415 Median 95% CI Proportion Not Progressed Months Accelerated Phase CML NProgression Study Study Censored +

Efficacy in Myeloid Blast Crisis Studies 002 and 006

34 Efficacy Results n (%) of Patients Study 002 N = 23 Study 006 N = 74 Hematologic Response Major (MaHR) Major (MaHR) 7 (30) 24 (32) Complete (CHR) Complete (CHR) 3 (13) 18 (24) No Evidence of Leukemia No Evidence of Leukemia 4 (17) 6 (8) Cytogenetic Response Major (MCyR) Major (MCyR) 8 (35) 22 (30) Complete (CCyR) Complete (CCyR) 6 (26) 20 (27) Loss of MaHR 20 Loss of MCyR 42 Myeloid Blast Phase CML

35 Progression-free Survival N2374 Number Progressed 1635 Median4.4 95% CI 2.6 – Proportion Not Progressed Months Censored + Myeloid Blast Phase CML NProgression Study Study

Efficacy in Lymphoid Blast Crisis and Ph+ ALL Studies 002 and 015

37 Efficacy Results n (%) of Patients Study 002 Study 015 L. Blast/Ph+ ALL N = 10 L. Blast N = 42 Ph+ ALL N = 36 Hematologic Response Major (MaHR) Major (MaHR) 5 (50) 13 (31) 15 (42) Complete (CHR) Complete (CHR) 3 (30) 11 (26) 11 (31) No Evidence of Leukemia No Evidence of Leukemia 2 (20) 2 (5) 4 (11) Cytogenetic Response Major (MCyR) Major (MCyR) 8 (80) 21 (50) 21 (58) Complete (CCyR) Complete (CCyR) 3 (30) 18 (43) 21 (58) Loss of MaHR 363 Loss of MCyR 6108 Lymphoid Blast Phase CML / Ph+ ALL

38 Progression-free Survival Proportion Not Progressed Months 002 LB/ALL 015 LB 015 ALL Censored Lymphoid Blast Phase CML / Ph+ ALL NProgressionMedian 95% CI Study 002 LB/ALL – 5.5 Study 015 ALL – 7.2 Study 015 LB – 4.3

39 H396R/PF359C/I/VE355GM351TT315IE255K/VY253H/FG250EM244V 7/216/162/107/150/192/1910/209/319/17MCyR 14/218/166/1012/150/198/1915/2019/3113/17MaHR P CA Hematologic Responses by Mutation Status 34 unique mutations 9 amino acid substitutions account for 68% of all BCR-ABL mutations

40 Summary of Efficacy Chronic Phase CML u High rate of major cytogenetic response in imatinib- resistant and imatinib-intolerant patients u Durable responses extending beyond 1 year u Progression-free survival at 6 months predictive of long-term benefit Advanced Disease (Accelerated, Blast, Ph+ ALL) u High rate of major hematologic responses u Durable, complete responses in Ph+ ALL u Long-term survivors identified at all stages including patients in blast transformation

Safety

42 Safety Overview Safety Database u 511 leukemic patients treated with dasatinib BID u Minimum 8 months of follow-up Major Findings u Myelosuppression, mostly thrombocytopenia u Fluid retention, including pleural effusion

43 Myelosuppression n (%) of Patients Chronic N = 208 Accelerated N = 118 M. Blast N = 97 L. Blast / Ph+ ALL N = 88 Solid Tumor N = 32 WBC <2.0 x 10 9 /L 50 (24) 71 (60) 65 (68) 60 (68) 0 ANC <1.0 x 10 9 /L 103 (50) 92 (78) 83 (86) 67 (79) 0 Platelets <50 x 10 9 /L 97 (47) 97 (82) 81 (84) 72 (82) 0

44 Time to Severe Thrombocytopenia Percent (%)

45 Adverse Reactions Related to Myelosuppression n (%) of Patients Chronic N = 208 Accelerated N = 118 M. Blast N = 97 L. Blast/ Ph+ ALL N = 88 Total N = 511 GI Hemorrhage 8 (4) 22 (19) 14 (14) 8 (9) 52 (10) CNS Hemorrhage 1 (<1) 00 2 (2) 3 (1) Febrile Neutropenia 3 (1) 10 (8) 5 (5) 10 (11) 28 (5) Severe Infections 5 (2) 8 (7) 6 (6) 9 (10) 28 (5) Pneumonia Pneumonia 4 (2) 5 (4) 1 (1) 4 (5) 14 (3) Sepsis Sepsis00 1 (1) 2 (<1) Aspergillosis Aspergillosis0 1 (1) 00 1 (<1)

46 Management of Myelosuppression n (%) of Patients Chronic N = 208 Accelerated N = 118 M. Blast N = 97 L. Blast/ Ph+ ALL N = 88 Transient Dose Interruption 106 (51) 55 (47) 26 (27) 11 (13) Median Duration (days) Dose Reduction 93 (45) 44 (37) 20 (21) 5 (6) Platelet Transfusion 46 (22) 71 (60) 72 (74) 54 (61) Red Cell Transfusion 63 (30) 100 (85) 87 (90) 61 (69) Hematopoietic Growth Factors 32 (15) 37 (31) 26 (27) 29 (33) Discontinuation 2 (1) 1 (1)

47 Most Common Non-hematologic Adverse Reactions n (%) of Patients Grade 1-4 Grade 3-4 Fluid Retention 223 (44) 42 (8) Diarrhea 179 (35) 20 (4) Rash 132 (26) 7 (1) Nausea 103 (20) 5 (1) Headache 121 (24) 5 (1) Fatigue 108 (21) 9 (2) Dyspnea 106 (21) 19 (4) Asthenia 82 (16) 13 (3) Musculoskeletal pain 77 (15) 4 (1) Vomiting 68 (13) 4 (1)

48 Fluid Retention n (%) of Patients N = 511 Any Fluid Retention 223 (44) Superficial Edema 144 (28) Pleural Effusion 108 (21) Others Pericardial Effusion Pericardial Effusion 14 (3) Congestive Heart Failure Congestive Heart Failure 12 (2) Pulmonary Edema Pulmonary Edema 10 (2) Cardiac Dysfunction Cardiac Dysfunction 7 (1) Pulmonary Hypertension Pulmonary Hypertension 5 (1)

49 Pleural Effusion n (%) of Patients Chronic N = 208 Accelerated N = 118 M. Blast N = 97 L. Blast/ Ph+ ALL N = 88 Drug-related 38 (18) 26 (22) 29 (30) 15 (17) Grade (3) 3 (3) 13 (13) 2 (2) Time to Event (days)

50 Management of Pleural Effusion n (%) of Patients with Events All Drug-related Events 108 Medical Intervention Diuretics 83 (77) Corticosteroids 37 (34) Dose Interruption 48 (44) Dose Reduction 8 (7) Invasive Procedures Thoracentesis 19 (18) Pleurodesis 1 (1) Discontinuation 4 (4)

51 Management of Other Events of Fluid Retention n (%) of Patients with Events All Drug-related Events 44 Medical Intervention Diuretics 34 (77) Corticosteroids 11 (25) Dose Interruption 17 (39) Dose Reduction 4 (9) Invasive Procedures Pericardial window 2 (5) Discontinuation 6 (14)

52 Effect on Cardiac Repolarization u Nonclinical evaluation –hERG IC 50 : 14,300 nM –No ECG change in telemetered monkeys u Clinical findings –Mean ∆ QTcF: 3–6 msec u QTc outlier analysis (serial ECGs in Phase II) –QTcF: 3/446 >500 msec on Day 8 –∆ QTcF: 13/441 >60 msec on Day 8 u Adverse events –9 AEs of QT prolongation –No arrhythmia associated with QT prolongation

53 Laboratory Abnormalities n (%) of Patients Grade 1-4 Grade 3-4 AST 321 (63) 17 (3) ALT 296 (58) 26 (5) Bilirubin 131 (26) 16 (3) Creatinine 175 (34) 5 (1) ↓ Ca (62) 50 (10) ↓ Mg (34) 1 (<1)

54 Dasatinib in Imatinib-intolerant Patients u 94 intolerant patients u Similar safety profile to the entire population –Myelosuppression –Fluid retention u Minimal cross-intolerance with imatinib –No recurrent hepatotoxicity or skin toxicity –Three patients developed the same grade 3 toxicity on dasatinib (nausea, diarrhea, fatigue)

55 Safety Summary u Myelosuppression –Predictable, frequently severe –Rarely complicated by severe bleeding or infection –Manageable by dose interruption, dose reduction and occasionally by transfusion u Fluid retention including pleural effusion –Common, likely related to PDGFR inhibition –Managed with diuretics, corticosteroids, dose interruptions and, occasionally, invasive procedures u Minimal hepatotoxicity u Other adverse events were usually mild to moderate

Clinical Perspective Hagop M. Kantarjian, MD Chairman & Professor, Leukemia Department MD Anderson

57 Chronic Phase CML – Imatinib-resistant u Poor prognosis after imatinib failure –Few cytogenetic responses –Poor survival: <2 years; <1 year with P-loop mutations u Limited treatment options: stem cell transplant, escalate imatinib, hydroxyurea, IFN- , investigational agents u Major benefit with dasatinib: –CHR 87% and MCyR >30% –Duration of response > 1 year

58 Chronic Phase CML – Imatinib-intolerant u Highest unmet medical need –No benefit from targeted therapy u Imatinib intolerance uncommon, but often associated with resistance u 67 patients with intolerance, mostly non-hematologic, treated –Hematologic and cytogenetic responses similar to those achieved with imatinib post-interferon –Responses durable; all patients progression-free (follow-up 6 to 20 months) u Minimal cross-intolerance

59 Accelerated Phase CML Post-imatinib Failure u Initial diagnosis of accelerated phase uncommon; most patients progress from chronic phase and are imatinib-resistant u Poor prognosis: median survival <1 yr –Limited options: hydroxyurea, intensive chemotherapy +/- stem cell transplant, investigational agents –No durable responses u Dasatinib highly effective –High rates of durable hematologic and cytogenetic response

60 Blast Phase CML Post-imatinib Failure u Almost all patients progressed to blast phase and were imatinib resistant u Very poor survival; rarely exceeds few months –Most had prior chemotherapy –Limited options: intensive chemotherapy, investigational therapy u Dasatinib induces durable responses unexpected with other therapeutic options

61 Ph+ ALL Post-imatinib Failure u Worst prognosis –No treatment options due to failure of prior therapies including chemotherapy and stem cell transplant –Expected survival less than 3 months u Dasatinib highly effective –Durable complete hematologic and cytogenetic responses –Duration of response > 4 months

62 Overall Safety u Most important safety issues myelosuppression and fluid retention u Potentially severe, but manageable with early interventions –Dose interruption –Dose reduction –Non-invasive interventions Growth factors for myelosuppressionGrowth factors for myelosuppression Diuretics and steroids for fluid retentionDiuretics and steroids for fluid retention

63 Dasatinib Benefit:Risk Potential u Benefits patients with CML and Ph+ ALL who have no other treatment options u Highly effective in all CML phases post- imatinib failure u Minimal cross-intolerance with imatinib u Myelosuppression predictable and manageable u Other toxicities (including pleural effusion) manageable with early intervention

Conclusion Donna Morgan Murray, PhD Bristol-Myers Squibb Global Regulatory Sciences

65 Proposed Indications for Dasatinib u Treatment of adults with chronic, accelerated, or blast phase chronic myeloid leukemia (CML) with resistance or intolerance to prior therapy including imatinib u Treatment of adults with Philadelphia chromosome ‑ positive (Ph+) acute lymphoblastic leukemia (ALL) and lymphoid blast chronic myeloid leukemia with resistance or intolerance to prior therapy