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

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.

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

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

Bosutinib in CP CML (2nd Line)a

Patient Characteristics (N = 294)

CharacteristicMedian [range],

or No. (%)Age, y 52.0 [18.0-91.0]Time from diagnosis, y 4.0 [0.1-17.8]

Duration of prior imatinib, y 2.3 [0-9.4]

Imatinib resistance 202 (69)Imatinib intolerance 92 (31)

Prior interferon 95 (32)

Prior stem cell transplant 8 (3)

Mutationsb 43 (45)aResults 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).b96 patients evaluated for mutations.

Bosutinib in CP CML (2nd Line) Bosutinib Administration

ParameterMedian [range],

or No. (%)

Duration of treatment, mo 13.7 [0.2-46.8]

Dose intensity, mg/day 454.1 [61.5-599.6]

Dose interruption 227 (77)

Dose reductiona 132 (45)

Dose escalation to 600 mg 33 (12)aDose 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

Response No. (%)Hematologica n = 109b

Overall 102 (94) Complete 99 (91)Cytogenetic n = 214b

Major 136 (64) Complete 106 (50)Molecular n = 151b

Major 79 (52) Complete 49 (32)aIncludes patients with unconfirmed hematologic response.bPatients 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 (2nd Line) Best Response

Bosutinib in CP CML (2nd Line) Best Response

ResponseNo. (%)

Imatinib resistant

Imatinib intolerant

Hematologica n = 75b n = 34b

Overall 69 (92) 33 (97) Complete 66 (88) 33 (97)Cytogenetic n = 158b n = 56b

Major 95 (60) 41 (73) Complete 73 (46) 33 (59)Molecular n = 108b n = 43b

Major 58 (54) 21 (49) Complete 32 (30) 17 (40)aIncludes patients with unconfirmed hematologic response.bPatients 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 (2nd Line) Time to Response

CCyR, complete cytogenetic response; MCyR, major cytogenetic response; CHR, complete hematologic response.aIncludes patients with unconfirmed hematologic response.

nMedian time to onset,

mo (95% CI) No. of events at Month 36

CCyR 214 12.3 (9.5-18.0) 106

MCyR 214 6.3 (6.0-9.1) 136

CHRa 109 0.8 (0.5-0.8) 99

100

9080

70

6050

40

302010

00 2 4 6 8 10 12

CCyR

Pro

bab

ility

of

resp

on

se (

%)

Time to response (months)

MCyRCHRa

28 30 32 34 3614 16 18 20 22 24 26

Bosutinib in CP CML (2nd Line) Duration of MCyR

nNo. (%) patients retaining MCyR

IM resistant 95 74 (78)

IM intolerant 41 35 (85)MCyR, major cytogenetic response; IM, imatinib.

100

9080

7060

50

40

30

20

10

00 2 4 6 8 10 12

IM resistant

IM intolerant

Pro

bab

ility

of

rem

ain

ing

MC

yR (

%)

Duration of MCyR (months)

14 16 18 20 22 24 26 28 30 32 34 36

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

• 19 different mutations identified in 43 of 96 (45%) patients tested

Mutation type,an/n evaluable (%)

CHR MCyR

Any 19/22 (86) 28/39 (72)

P-loop 4/4 (100) 6/9 (67)

Non–P-loop 15/18 (83) 22/30 (73)

No mutation 26/28 (93) 22/38 (58)aPatients 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.

Bosutinib in CP CML (2nd Line) Response by Individual Mutations

0

1

2

3

4

5

6

7L

248V

G25

0E

Y25

3F

Y25

3H

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5K

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4V

F31

1L

T31

5I

F31

7L

N33

1S

M35

1T

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5G

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Evaluable patients

CHR

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Evaluable patients

MCyR

CHR

MCyR

CHR, complete hematologic response; MCyR, major cytogenetic response.

Bosutinib in CP CML (2nd Line) Progression-free Survival

100

90

80

7060

50

40

30

20

10

0

IM resistant

IM intolerant

Pro

bab

ility

of

PF

S (

%)

Time to progression (months)

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

n Median PFSNo. (%) patients progression

free at Month 24

IM resistant 202 Not reached 155 (77)

IM intolerant 92 Not reached 79 (86)PFS, progression-free survival; IM, imatinib.

Bosutinib in CP CML (2nd Line) Overall Survival

100

90

80

7060

50

4030

20

10

0

IM resistant

IM intolerant

Pro

bab

ility

of

OS

(%

)

Time to death (months)

n Median OSNo. (%) patients alive

at Month 24

IM resistant 202 Not reached 186 (92)

IM intolerant 92 Not reached 91 (99)OS, overall survival; IM, imatinib.

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

Adverse eventNo. (%)

All grades Grade 3-4Diarrhea 247 (84) 26 (9)Nausea 129 (44) 5 (2)Vomiting 105 (36) 9 (3)Rash 100 (34) 25 (9)Abdominal pain 63 (21) 3 (1)Fatigue 61 (21) 2 (1)Pyrexia 60 (20) 1 (1)

Cough 47 (16) 0

Headache 42 (14) 0

Arthralgia 39 (13) 1 (1)

Decreased appetite 36 (12) 2 (1)

Nasopharyngitis 33 (11) 0

Constipation 31 (11) 1 (1)

Asthenia 31 (11) 5 (2)

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

Laboratory abnormality No. (%)

Thrombocytopenia 72 (24)

Neutropenia 47 (16)

Anemia 36 (12)

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

Abnormalities

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

Laboratory abnormality No. (%)

Hypermagnesemia 34 (12)Elevated ALT 30 (10)Hypophosphatemia 23 (8)Elevated lipase 21 (7)Elevated uric acid 16 (5)Elevated AST 14 (5)Hypocalcemia 10 (3)Hypomagnesemia 10 (3)Hyperglycemia 8 (3)Elevated INR 7 (2)Elevated potassium 7 (2)

Feature

No. (%)Imatinib resistant(n = 202)

Imatinib intolerant(n = 92)

All patients(n = 294)

Discontinued treatment 94 (47) 45 (49) 139 (47)Adverse event 32 (16) 25 (27) 57 (19)Disease progression 31 (15) 5 (5) 36 (12)Unsatisfactory response 12 (6) 3 (3) 15 (5)Patient request 8 (4) 5 (5) 13 (4)Death 5 (2) 0 5 (2)Investigator request 1 (1) 3 (3) 4 (1)Lost to follow-up 2 (1) 0 2 (1)Other 3 (2) 4 (4) 7 (2)

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

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

• 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