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
E25
5K
M24
4V
F31
1L
T31
5I
F31
7L
N33
1S
M35
1T
E35
5G
E35
5G/
M24
4V
F35
9I
F35
9V
H39
6P
H39
6R
I432
T
E45
3K
Nu
mb
er
of
pa
tie
nts
Evaluable patients
CHR
0
1
2
3
4
5
6
7
L24
8V
G25
0E
Y25
3F
Y25
3H
E25
5K
M24
4V
F31
1L
T31
5I
F31
7L
N33
1S
M35
1T
E35
5G
E35
5G/
M24
4V
F35
9I
F35
9V
H39
6P
H39
6R
I432
T
E45
3K
Nu
mb
er
of
pa
tie
nts
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