J. E. Cortes, H. M. Kantarjian, T. H. Brümmendorf,

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. 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.

3. Bosutinib in CP CML (2nd 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

4. Bosutinib in CP CML (2nd 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

5. Bosutinib in CP CML (2nd Line)a Patient Characteristics (N = 294)

6. Bosutinib in CP CML (2nd Line) Bosutinib Administration • Median follow-up was 23.8 mo (range, 0.3-51.0 mo) • Data cut-off date : February 22, 2010

7. Bosutinib in CP CML (2nd Line) Best Response

8. Bosutinib in CP CML (2nd Line) Best Response

9. 100 90 80 70 60 Probability of response (%) 50 40 30 CCyR MCyR 20 CHRa 10 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Time to response (months) Bosutinib in CP CML (2nd Line) Time to Response CCyR, complete cytogenetic response; MCyR, major cytogenetic response; CHR, complete hematologic response. aIncludes patients with unconfirmed hematologic response.

10. Bosutinib in CP CML (2nd Line) Duration of MCyR 100 90 80 70 60 Probability of remaining MCyR (%) 50 40 30 IM resistant 20 IM intolerant 10 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Duration of MCyR (months)

11. Bosutinib in CP CML (2nd Line) Response by Mutation Status

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

13. Bosutinib in CP CML (2nd Line) Progression-free Survival 100 90 80 70 60 Probability of PFS (%) 50 40 30 IM resistant 20 IM intolerant 10 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Time to progression (months)

14. Bosutinib in CP CML (2nd Line) Overall Survival 100 90 80 70 60 Probability of OS (%) 50 40 30 IM resistant 20 IM intolerant 10 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Time to death (months)

15. Bosutinib in CP CML (2nd Line) Treatment-emergent Adverse Events

16. Bosutinib in CP CML (2nd Line) Grade 3-4Hematologic Laboratory Abnormalities

17. Bosutinib in CP CML (2nd Line) Other Grade 3-4 Laboratory Abnormalities

18. Bosutinib in CP CML (2nd Line) Discontinuation From Treatment

19. Bosutinib in CP CML (2nd 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

20. Acknowledgments • 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