Transcript Safety and Efficacy of Bosutinib (SKI

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)
Characteristic
Age, y
Time from diagnosis, y
Duration of prior imatinib, y
Imatinib resistance
Imatinib intolerance
Prior interferon
Prior stem cell transplant
Mutationsb
aResults
Median [range],
or No. (%)
52.0 [18.0-91.0]
4.0 [0.1-17.8]
2.3 [0-9.4]
202 (69)
92 (31)
95 (32)
8 (3)
43 (45)
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
Parameter
Duration of treatment, mo
Dose intensity, mg/day
Dose interruption
Dose reductiona
Dose escalation to 600 mg
aDose
•
•
Median [range],
or No. (%)
13.7 [0.2-46.8]
454.1 [61.5-599.6]
227 (77)
132 (45)
33 (12)
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
Bosutinib in CP CML (2nd Line)
Best Response
Response
Hematologica
Overall
Complete
Cytogenetic
Major
Complete
Molecular
Major
Complete
No. (%)
n = 109b
102 (94)
99 (91)
n = 214b
136 (64)
106 (50)
n = 151b
79 (52)
49 (32)
aIncludes patients with unconfirmed hematologic response.
bPatients with CHR, CCyR, or CMR at baseline and patients lacking
either a baseline or a postbaseline assessment are considered non-evaluable for the respective response.
Bosutinib in CP CML (2nd Line)
Best Response
Response
Hematologica
Overall
Complete
Cytogenetic
Major
Complete
Molecular
Major
Complete
No. (%)
Imatinib
Imatinib
resistant
intolerant
n = 75b
n = 34b
69 (92)
33 (97)
66 (88)
33 (97)
n = 158b
n = 56b
95 (60)
41 (73)
73 (46)
33 (59)
n = 108b
n = 43b
58 (54)
21 (49)
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 postbaseline assessment are considered non-evaluable for the respective response.
Probability of response (%)
Bosutinib in CP CML (2nd Line)
Time to Response
100
90
80
70
60
50
40
30
20
10
CCyR
MCyR
CHRa
0
0
CCyR
MCyR
CHRa
2
4
n
214
214
109
6
8
10 12 14 16 18 20 22 24 26 28 30 32 34 36
Time to response (months)
Median time to onset,
mo (95% CI)
12.3 (9.5-18.0)
6.3 (6.0-9.1)
0.8 (0.5-0.8)
No. of events at Month 36
106
136
99
CCyR, complete cytogenetic response; MCyR, major cytogenetic response; CHR, complete hematologic response.
aIncludes patients with unconfirmed hematologic response.
Probability of remaining MCyR (%)
Bosutinib in CP CML (2nd Line)
Duration of MCyR
100
90
80
70
60
50
40
30
20
10
IM resistant
IM intolerant
0
0
2
4
6
8
10 12 14 16 18 20 22 24 26 28 30 32 34 36
Duration of MCyR (months)
IM resistant
IM intolerant
n
95
41
No. (%) patients
retaining MCyR
74 (78)
35 (85)
MCyR, major cytogenetic response; IM, imatinib.
Bosutinib in CP CML (2nd Line)
Response by Mutation Status
• 19 different mutations identified in 43 of 96 (45%)
patients tested
Mutation
type,a
Any
P-loop
Non–P-loop
No mutation
aPatients
n/n evaluable (%)
CHR
MCyR
19/22 (86)
28/39 (72)
4/4 (100)
6/9 (67)
15/18 (83)
22/30 (73)
26/28 (93)
22/38 (58)
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.
CHR, complete hematologic response; MCyR, major cytogenetic response.
H396P
H396R
H396P
H396R
E453K
E453K
I432T
F359V
F359V
I432T
F359I
N331S
F317L
F359I
0
E355G/
M244V
1
E355G/
M244V
2
E355G
3
E355G
4
M351T
MCyR
M351T
N331S
Evaluable patients
MCyR
F317L
5
T315I
F311L
M244V
E255K
Y253H
Y253F
Evaluable patients
CHR
T315I
F311L
M244V
5
E255K
6
Y253H
7
Y253F
6
G250E
L248V
Number of patients
7
G250E
L248V
Number of patients
Bosutinib in CP CML (2nd Line)
Response by Individual Mutations
CHR
4
3
2
1
0
Bosutinib in CP CML (2nd Line)
Progression-free Survival
Probability of PFS (%)
100
90
80
70
60
50
40
30
IM resistant
IM intolerant
20
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)
IM resistant
IM intolerant
n
202
92
Median PFS
Not reached
Not reached
PFS, progression-free survival; IM, imatinib.
No. (%) patients progression
free at Month 24
155 (77)
79 (86)
Bosutinib in CP CML (2nd Line)
Overall Survival
Probability of OS (%)
100
90
80
70
60
50
40
30
IM resistant
IM intolerant
20
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)
IM resistant
IM intolerant
n
202
92
OS, overall survival; IM, imatinib.
Median OS
Not reached
Not reached
No. (%) patients alive
at Month 24
186 (92)
91 (99)
Bosutinib in CP CML (2nd Line)
Treatment-emergent Adverse Events
Adverse event
Diarrhea
Nausea
Vomiting
Rash
Abdominal pain
Fatigue
Pyrexia
Cough
Headache
Arthralgia
Decreased appetite
Nasopharyngitis
Constipation
Asthenia
No. (%)
All grades
247 (84)
129 (44)
105 (36)
100 (34)
63 (21)
61 (21)
60 (20)
47 (16)
42 (14)
39 (13)
36 (12)
33 (11)
31 (11)
31 (11)
Grade 3-4
26 (9)
5 (2)
9 (3)
25 (9)
3 (1)
2 (1)
1 (1)
0
0
1 (1)
2 (1)
0
1 (1)
5 (2)
Bosutinib in CP CML (2nd Line)
Grade 3-4 Hematologic Laboratory
Abnormalities
Laboratory abnormality
No. (%)
Thrombocytopenia
72 (24)
Neutropenia
47 (16)
Anemia
36 (12)
Bosutinib in CP CML (2nd Line)
Other Grade 3-4 Laboratory Abnormalities
Laboratory abnormality
No. (%)
Hypermagnesemia
Elevated ALT
Hypophosphatemia
Elevated lipase
Elevated uric acid
Elevated AST
Hypocalcemia
Hypomagnesemia
Hyperglycemia
Elevated INR
Elevated potassium
34 (12)
30 (10)
23 (8)
21 (7)
16 (5)
14 (5)
10 (3)
10 (3)
8 (3)
7 (2)
7 (2)
Bosutinib in CP CML (2nd Line)
Discontinuation From Treatment
No. (%)
Imatinib Imatinib
All
Feature
resistant intolerant patients
(n = 202) (n = 92) (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)
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
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