AACR 2014 - Efficacy of Cabozantinib Combinations

EVALUATION OF CABOZANTINIB IN COMBINATION WITH ABIRATERONE, ENZALUTAMIDE OR DOCETAXEL IN CASTRATION‐RESISTANT PROSTATE CANCER IN VIVO
Holly M Nguyen, Lisha G Brown Jessica Olson , Dana T Aftab*, Robert L Vessella and Eva Corey
University of Washington, Seattle, WA; * Exelixis, Inc., South San Francisco, CA
400
200
0
1
2
3
Blood was drawn weekly and serum PSA levels were determined using AxSym Total PSA
Assay ( Abbott LAboratories()
2
3
2
4
6
8
4
10
12
14
16
TV (mm3)
18
0
2
4
6
8
10
400
2
3
Percent survival
60
40
20
DOC
CABO
DOC + CABO
2
3
4
0
0
5
1
2
3
4
30
PSA (ng/ml)
PSA (ng/ml)
25
20
15
10
5
20
15
5
1
2
3
0
4
40
20
0
20
5
10
1
2
3
4
MEDIAN SURVIVAL TIME
(weeks)
6.5 vs 15.5
16 vs 15.5
6.8 vs 15
16 vs 15

Abiraterone acetate (0.5 mmol/kg = 196 mg/kg) was administered five days a week by oral
gavage


Animals were treated for four weeks and followed for additional six weeks after cessation of
the therapy
Small subset of animals was treated for up to 18 weeks to evaluate long term activity of
cabozantinib and its combinations
HR
8.69
1.26
8.32
1.084
1
2
3
4
Time (Weeks Post Enrollment)
Cabo 10 mg/kg, 4 weeks, was well tolerated, with no apparent negative side effects
LuCaP 96CR
CONTROL
ENZ
CABO
ENZ + CABO
1400
1200
800
600
STOP TX
1200
1000
TV (mm3)
STOP TX
1000
TV (mm3)
TV (mm3)
DOC + CABO
ENZ + CABO
1400
800
600
800
600
400
200
200
200
0
0
0
2
4
6
8
2
4
6
8
10
0
80
60
40
20
0
2
4
6
2
4
8
10
100
80
80
60
40
20
ABI+CABO
ARMS COMPARED
ABI vs ABI + CABO
CABO vs ABI +CABO
ENZ vs ENZ + CABO
CABO vs ENZ +CABO
DOC vs DOC + CABO
CABO vs DOC + CABO
8
10
2
4
6
800
600
400
200
0
1
2
3
Time (Weeks Post Enrollment)
4
0
1
2
3
4
5
6
Time (Weeks Post Enrollment)
 Single‐agent cabo showed tumor inhibitory activity at 10 mg/kg, and reduced
activity at 3 mg/kg
60
40
20
0
0
8
10
Time (Weeks Post Enrollment)
CONTROL
ENZ
CABO
ENZ + CABO
CONTROL
ABI
CABO
6
1000
DOC + CABO
100
0
0
400
0
Time (Weeks Post Enrollment)
ENZ + CABO
ABI + CABO
100
600
0
Time (Weeks Post Enrollment)
Time (Weeks Post Enrollment)
800
200
400
0
10
STOP TX
1000
400
0
TV (mm3)
ABI + CABO
1400
1200
TV (mm3)
1200
Time (Weeks Post Enrollment)
The project was funded by Exelixis, Inc., South San Francisco, CA. Development and characterization of
LuCaP models was supported by Lucas Foundation and PCF.
P
0.0039
0.76
0.008
0.92
Animals were treated up to 18 weeks with cabo 10 mg/kg +/‐ other agents; no negative side effects were observed
0
Percent survival
Docetaxel (10 mg/kg) was administered weekly by IP injection
20
0
Time (Weeks Post Enrollment)
Time (Weeks Post Enrollment)
Percent survival

15
Time (Weeks Post Enrollment)
10
0
0
15
ENZ vs ENZ + CABO
CABO vs ENZ +CABO
DOC vs DOC + CABO
CABO vs DOC + CABO
DOC + CABO
25
5
10
ARMS COMPARED
Time (Weeks Post Enrollment)
30
10
60
0
0
0
1
ENZ + CABO
15
80
Time (Weeks Post Enrollment)
Time (Weeks Post Enrollment)
20
Percent survival
Enzalutamide (50 mg/kg) was administered five days a week by oral gavage
18
200
0
4
80
400
0
1
Control
600
200
200
1200

16
DOC + CABO
1000
Cabozantinib (10 mg/kg or 3 mg/kg) was administered five days a week by oral gavage
14
100
LuCaP 35CR

12
Time (Weeks Post Enrollment)
ENZ + CABO
Percent survival
Control
ENZ
CABO
ENZ + CABO
800
TV (mm3)
TV (mm3)
400
PSA (ng/ml)
DOC + CABO
600
TV (mm3)
Control
ABI
CABO
ABI + CABO
0

1
ENZ + CABO
800
25
Tumor volume was measured twice weekly
400
Time (Weeks Post Enrollment)
Decreases in serum PSA with abi were not associated with reduced tumor growth in this model
30

600
0
0
Time (Weeks Post Enrollment)
ABI + CABO
Animals were randomized into groups after tumor exceeded 150 mg
CABO
DOC + CABO
800
200
0
0
4
Time (Weeks Post Enrollment)

Control
DOC
1000
100
0
Tumor bits were implanted subcutaneously into castrated male mice
400
200
10
Time (Weeks Post Enrollment)
0

15
600
1200
0
0
600
LuCaP 35CR and LuCaP 96CR were used in these studies
20
800
5
ABI + CABO

TV (mm3)
600
Control
ENZ
CABO
ENZ + CABO
1000
25
PSA (ng/ml)
Control
MDV3100
ABI
CABO
DOC
800
 To evaluate effects of cabo in combination with abi, enz or doc on CRPC xenograft
tumors in vivo
1200
30
800
TV (mm3)
 Cabozantinib (cabo) is an inhibitor of tyrosine kinases including MET, VEGFR2,
RET, KIT, and AXL
 Cabo has shown activity as monotherapy in clinical investigations in castration‐
resistant prostate cancer (CRPC)
 New second‐generation hormonal therapy agents abiraterone (abi) and
enzalutamide (enz), and standard chemotherapy docetaxel (doc) provide survival
benefits for patients with CRPC
 Despite these survival benefits, CRPC is still an incurable disease
 Clinical investigations of cabo combined with other agents are planned or
underway
DOC + CABO
ENZ + CABO
PSA
TUMOR VOLUME
MEDIAN SURVIVAL TIME
(weeks)
5.5 vs 7
7 vs 7
6.8 vs 9
7 vs 9
7.5 vs 8.3
7 vs 8.3
0
2
4
6
8
Time (Weeks Post Enrollment)
CONTROL
DOC
CABO
DOC+CABO
P
HR
0.052
0.93
0.0008
0.02
0.30
0.027
2.4
1.0
5.8
3.1
1.6
2.9
10
 Addition of cabo (10 mg/kg) to enz or doc treatment resulted in more
pronounced tumor suppression vs these agents as monotherapy after 4 weeks of
treatment
 In studies with abi, decreases in serum PSA were not associated with decreased
tumor volume
 Animals treated with cabo + enz for 4 weeks exhibited improved survival over
treatment with the single agents
 Addition of cabo to enz or doc for long term treatment resulted in better tumor
inhibition and longer survival than enz or doc as monotherapy, with no apparent
development of resistance

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