1. Safety and Efficacy of Bosutinib (SKI-606) in Patients With Chronic Phase (CP) Chronic Myeloid Leukemia (CML) Following Resistance or Intolerance to Imatinib J. E. Cortes, H. M. Kantarjian, T. H. Brümmendorf, H. J. Khoury, D-W. Kim, A. Turkina, A. Volkert, J. Wang, S. Arkin, and C. Gambacorti-Passerini University of Texas M. D. Anderson Cancer Center, Houston, TX, USA; Universitäts-Klinikum Hamburg-Eppendorf, Hamburg, Germany; Universitäts-Klinikum Aachen, Aachen, Germany; Emory University School of Medicine, Atlanta, GA, USA; Seoul St. Mary’s Hospital, Seoul, South Korea; Hematology Research Center, Moscow, Russia; Pfizer Inc, Cambridge, MA, USA; University of Milan Bicocca, Monza, Italy

2. Boschelli DH, et al. J Med Chem. 2005;48:3891-3902; Golas JM, et al. Cancer Res. 2003;63:375-381; Golas JM, et al. Cancer Res. 2005;65:5358-5364;Puttini M, et al. Cancer Res. 2006;66:11314-22. N CN HN ClCl O O ON N Src enzyme (ELISA) IC 50 = 1.2 nM Src enzyme (Lance) IC 50 = 3.8 nM Abl enzyme IC 50 = 1.4 nM K562 cell IC 50 = 20 nM KU812 cell IC 50 = 4.3 nM Courtesy of L. Scapozza and A. Shaheen, University of Geneva, Switzerland. Bosutinib: A Dual Inhibitor of Src and Abl Kinases

3. Effect of Bosutinib Versus Imatinib on Cell Proliferation IC 50 ± SE (nmol/L) BosutinibImatinib p210 Ba/F313 ± 4401 ± 70 D276G Ba/F325 ± 151,147 ± 231 Y253F Ba/F340 ± 221,888 ± 979 E255K Ba/F33943,174 ± 1,211 T315I Ba/F31,800 ± 850  10,000 Tel-PDGFRβ Ba/F3370 ± 1803.4 ± 0.9 c-KIT exon 13 mutant GIST8826,00029.5 c-KIT G560V HCM1 560 950 ± 45019 Puttini M, et al. Cancer Res. 2006;66:11314-22.

4. Summary of Bosutinib Preclinical Activity Orally bioavailable Potent dual Src/Abl inhibitor Minimal inhibitory activity against PDGFR and c-KIT Inhibits Bcr-Abl signaling in CML cells Active against imatinib-resistant mutants of Bcr-Abl, except T315I Boschelli DH, et al. J Med Chem. 2005;48:3891-3902.; Golas JM, et al. Cancer Res. 2003;63:375-381. Puttini M, et al. Cancer Res. 2006;66:11314-22.

5. Bosutinib in CP CML (2 nd Line) Study Design Open-label, continuous oral daily dosing Part 1: Dose escalation –Patients with chronic phase CML –Imatinib resistance only –Bosutinib dose: 400, 500, or 600 mg/day Part 2: Efficacy and safety –Patients with Ph+ CML in any phase –Imatinib intolerance or resistance –Bosutinib dose: 500 mg/day

6. Bosutinib in CP CML (2 nd Line) Definitions and Assessments Population: – Imatinib resistant: Received  600 mg/day imatinib, and No CHR by 3 months, cytogenetic response by 6 months, or MCyR by 12 months; or loss of response – Imatinib intolerant: Grade 4 hematologic toxicity >7 days Grade  3 non-hematologic toxicity Persistent grade 2 toxicity not responding to adequate management and/or dose adjustments Follow-up: – Cytogenetics every 3 months – PCR every month for 3 months, then every 3 months

7. Bosutinib in CP CML (2 nd Line) a Patient Characteristics (N = 294) Characteristic Median [range], or No. (%) Age, y52.0 [18.0-91.0] Time from diagnosis, y4.0 [0.1-17.8] Duration of prior imatinib, y 2.3 [0-9.4] Imatinib resistance202 (69) Imatinib intolerance92 (31) Prior interferon95 (32) Prior stem cell transplant8 (3) Mutations b 43 (45) a Results for bosutinib in CP CML following failure of >1 Abl kinase inhibitor and in advanced Ph+ CML are included in other analyses (HJ Khoury and C Gambacorti-Passerini). b 96 patients evaluated for mutations.

8. Bosutinib in CP CML (2 nd Line) Bosutinib Administration Parameter Median [range], or No. (%) Duration of treatment, mo13.7 [0.2-46.8] Dose intensity, mg/day454.1 [61.5-599.6] Dose interruption227 (77) Dose reduction a 132 (45) Dose escalation to 600 mg33 (12) a Dose reductions due to adverse events. Median follow-up was 23.8 mo (range, 0.3-51.0 mo) Data cut-off date : February 22, 2010

9. ResponseNo. (%) Hematologic a n = 109 b Overall102 (94) Complete99 (91) Cytogeneticn = 214 b Major136 (64) Complete106 (50) Molecularn = 151 b Major79 (52) Complete49 (32) a Includes patients with unconfirmed hematologic response. b Patients with CHR, CCyR, or CMR at baseline and patients lacking either a baseline or a post- baseline assessment are considered non-evaluable for the respective response. Bosutinib in CP CML (2 nd Line) Best Response

10. Response No. (%) Imatinib resistant Imatinib intolerant Hematologic a n = 75 b n = 34 b Overall69 (92)33 (97) Complete66 (88)33 (97) Cytogeneticn = 158 b n = 56 b Major95 (60)41 (73) Complete73 (46)33 (59) Molecularn = 108 b n = 43 b Major58 (54)21 (49) Complete32 (30)17 (40) a Includes patients with unconfirmed hematologic response. b Patients with CHR, CCyR, or CMR at baseline and patients lacking either a baseline or a post- baseline assessment are considered non-evaluable for the respective response.

11. Bosutinib in CP CML (2 nd Line) Time to Response CCyR, complete cytogenetic response; MCyR, major cytogenetic response; CHR, complete hematologic response. a Includes patients with unconfirmed hematologic response. n Median time to onset, mo (95% CI)No. of events at Month 36 CCyR21412.3 (9.5-18.0)106 MCyR2146.3 (6.0-9.1)136 CHR a 1090.8 (0.5-0.8)99 100 90 80 70 60 50 40 30 20 10 0 02468 12 CCyR Probability of response (%) Time to response (months) MCyR CHR a 283032343614161820222426

12. Bosutinib in CP CML (2 nd Line) Time to Response (cont) CCyR, complete cytogenetic response; MCyR, major cytogenetic response; CHR, complete hematologic response. a Includes patients with unconfirmed hematologic response. MCyR, n = 214 CHR a, n = 109 CCyR, n = 214 100 90 80 70 60 50 40 30 20 10 0 61218 Probability of response (%) Time to response (months) 243036 25% 41% 91% 40% 57% 91% 46% 61% 91% 48% 63% 91% 49% 63% 91% 50% 64% 91%

13. Bosutinib in CP CML (2 nd Line) Duration of MCyR n No. (%) patients retaining MCyR IM resistant9574 (78) IM intolerant4135 (85) MCyR, major cytogenetic response; IM, imatinib. 100 90 80 70 60 50 40 30 20 10 0 02468 12 IM resistant IM intolerant Probability of remaining MCyR (%) Duration of MCyR (months) 141618202224262830323436

14. Bosutinib in CP CML (2 nd Line) Response by Mutation Status 19 different mutations identified in 43 of 96 (45%) patients tested Mutation type, a n/n evaluable (%) CHRMCyR Any19/22 (86)28/39 (72) P-loop4/4 (100)6/9 (67) Non–P-loop15/18 (83)22/30 (73) No mutation26/28 (93)22/38 (58) a Patients with complete hematologic, cytogenetic, or molecular responses at baseline and patients lacking both a baseline and post-baseline assessment are considered non-evaluable for the respective response.

15. Bosutinib in CP CML (2 nd Line) Response by Individual Mutations CHR MCyR CHR, complete hematologic response; MCyR, major cytogenetic response.

16. Bosutinib in CP CML (2 nd Line) Progression-free Survival 100 90 80 70 60 50 40 30 20 10 0 IM resistant IM intolerant Probability of PFS (%) Time to progression (months) 024681012141618202224262830323436 nMedian PFS No. (%) patients progression free at Month 24 IM resistant202Not reached155 (77) IM intolerant92Not reached79 (86) PFS, progression-free survival; IM, imatinib.

17. Bosutinib in CP CML (2 nd Line) Overall Survival 100 90 80 70 60 50 40 30 20 10 0 IM resistant IM intolerant Probability of OS (%) Time to death (months) nMedian OS No. (%) patients alive at Month 24 IM resistant202Not reached186 (92) IM intolerant92Not reached91 (99) OS, overall survival; IM, imatinib. 024681012141618202224262830323436

18. Adverse event No. (%) All gradesGrade 3-4 Diarrhea247 (84)26 (9) Nausea129 (44)5 (2) Vomiting105 (36)9 (3) Rash100 (34)25 (9) Abdominal pain63 (21)3 (1) Fatigue61 (21)2 (1) Pyrexia60 (20) 1 (  1) Cough47 (16)0 Headache42 (14)0 Arthralgia39 (13) 1 (  1) Decreased appetite36 (12)2 (1) Nasopharyngitis33 (11)0 Constipation31 (11) 1 (  1) Asthenia31 (11)5 (2) Bosutinib in CP CML (2 nd Line) Treatment-emergent Adverse Events

19. Bosutinib in CP CML (2 nd Line) Gastrointestinal Adverse Events Parameter No. (%) DiarrheaNauseaVomiting Patients with event247 (84)129 (44)105 (36) Median time to onset, d258 Median duration, d25 [1-654]10 [1-446]3 [1-170] Resolved212 (86)117 (91)101 (96) Received Rx for AE157 (64)49 (38)32 (30) Required dose reduction13 (5)6 (5)7 (7) Required dose interruption31 (13)8 (6)14 (13) Discontinued treatment5 (2) 1 (  1) 4 (4)

20. Bosutinib in CP CML (2 nd Line) Other Adverse Events of Interest Pleural effusion –Observed in 2 (  1%) patients (all grades) –No grade 3-4 events were reported Prolongation of QTcF interval –On treatment: 8.6% had grade 1-2; 0.3% had grade 3-4 –At treatment completion: 2% had grade 1-2; 0% had grade 3-4

21. Laboratory abnormalityNo. (%) Thrombocytopenia72 (24) Neutropenia47 (16) Anemia36 (12) Bosutinib in CP CML (2 nd Line) Grade 3-4 Hematologic Laboratory Abnormalities

22. Bosutinib in CP CML (2 nd Line) Other Grade 3-4 Laboratory Abnormalities Laboratory abnormalityNo. (%) Hypermagnesemia34 (12) Elevated ALT30 (10) Hypophosphatemia23 (8) Elevated lipase21 (7) Elevated uric acid16 (5) Elevated AST14 (5) Hypocalcemia10 (3) Hypomagnesemia10 (3) Hyperglycemia8 (3) Elevated INR7 (2) Elevated potassium7 (2)

23. Feature No. (%) Imatinib resistant (n = 202) Imatinib intolerant (n = 92) All patients (n = 294) Discontinued treatment94 (47)45 (49)139 (47) Adverse event32 (16)25 (27)57 (19) Disease progression31 (15)5 (5)36 (12) Unsatisfactory response12 (6)3 (3)15 (5) Patient request8 (4)5 (5)13 (4) Death5 (2)0 Investigator request 1 (  1) 3 (3)4 (1) Lost to follow-up2 (1)0 2 (  1) Other3 (2)4 (4)7 (2) Bosutinib in CP CML (2 nd Line) Discontinuation From Treatment

24. Bosutinib in CP CML (2 nd Line) Conclusions Clinical efficacy in patients with CP CML resistant or intolerant to imatinib (CCyR 50%) Responses across wide variety of Bcr-Abl mutations Duration of response requires further follow-up Favorable toxicity profile –Self-limiting gastrointestinal adverse events –Low rates of hematologic toxicity –Minimal fluid retention

25. We would like to thank all of the participating patients and their families, as well as the global network of investigators, research nurses, study coordinators, and operations staff Principal investigators: USA: L. Akard, E. Asatiani, J. Cortes, A. Galvez, J. Glass, J. Liesveld, D. Liu, H. J. Khoury, J. McCarty, M. Maris, A. Rapoport, R. Silver, D. Snyder, M. Wetzler; CANADA: S. Assouline, M. Seftel, J. Sutherland, R. Turner; ITALY: M. Baccarani, C. Gambacorti, G. Saglio; GERMANY: T. Brümmendorf, T. Fischer, A. Hochhaus, A. Kiani; ARGENTINA: E. Bullorsky, G. D. Kusminsky, J. Milone; INDIA: M. Chandy; RUSSIA: A. Golenkov, I. Krylova, Y. Shatokhin, A. Turkina, A. Zaritskey, T. Zagoskina; SPAIN: F. Cervantes, J. C. Hernandez Boluda, J. L. Steegmann; AUSTRALIA: S. Durrant, T. Hughes, A. Spencer; NORWAY: H. Hjorth-Hansen; KOREA: D-W. Kim, J. Lee; HONG KONG: R. Liang, H. Liu; CHINA: J. Jin, L. Qiu, Z. Shen, L. Yu, Y. Zhao; SOUTH AFRICA: V. Louw, N. Novitzky, P. Ruff; HUNGARY: T. Masszi; NETHERLANDS: G. Ossenkoppele, E. Vellenga; FINLAND: K. Porkka; AUSTRIA: J. Thaler Study 3160A4-200 (ClinicalTrials.gov number NCT00261846) was supported by Pfizer Inc (formerly Wyeth Research) Editorial assistance was provided by Kimberly Brooks, PhD, of MedErgy and funded by Pfizer Inc Acknowledgments