U.S. patent application number 17/468103 was filed with the patent office on 2022-01-06 for method of treating renal cell carcinoma using n-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-n?-(4-fluorophenyl)cyclopropa- ne-1,1-dicarboxamide, (2s)-hydroxybutanedioate.
The applicant listed for this patent is Exelixis, Inc.. Invention is credited to Dana T. Aftab, Alan Arroyo, Mark Dean, Colin Hessel, Steven Lacy, Dale Miles, Christian Scheffold, Gisela Schwab.
Application Number | 20220000857 17/468103 |
Document ID | / |
Family ID | |
Filed Date | 2022-01-06 |
United States Patent
Application |
20220000857 |
Kind Code |
A1 |
Aftab; Dana T. ; et
al. |
January 6, 2022 |
Method of Treating Renal Cell Carcinoma Using
N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N?-(4-fluorophenyl)cyclopropa-
ne-1,1-dicarboxamide, (2S)-hydroxybutanedioate
Abstract
The present disclosure relates to a method of treating advanced
renal cell carcinoma (RCC) in human patients who have received
prior anti-angiogenic therapy using CABOMETYX, a kinase
inhibitor.
Inventors: |
Aftab; Dana T.; (San Rafael,
CA) ; Schwab; Gisela; (Hayward, CA) ; Hessel;
Colin; (Redwood City, CA) ; Scheffold; Christian;
(Palo Alto, CA) ; Lacy; Steven; (San Mateo,
CA) ; Miles; Dale; (Sunnyvale, CA) ; Arroyo;
Alan; (Danville, CA) ; Dean; Mark; (San
Francisco, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Exelixis, Inc. |
Alameda |
CA |
US |
|
|
Appl. No.: |
17/468103 |
Filed: |
September 7, 2021 |
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11141413 |
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International
Class: |
A61K 31/47 20060101
A61K031/47; A61K 31/16 20060101 A61K031/16; A61P 35/00 20060101
A61P035/00; A61K 9/20 20060101 A61K009/20; A61K 9/28 20060101
A61K009/28 |
Claims
1. A method of treating advanced renal cell carcinoma with or
without bone metastases in a human patient who has received prior
anti-angiogenic therapy, comprising administering to the patient an
amount of cabozantinib or a pharmaceutically acceptable salt
thereof, wherein progression-free survival (PFS) and one or both of
overall survival (OS) and objective response rate (ORR) are
extended as compared to patients who have received prior
anti-angiogenic therapy, wherein the prior anti-angiogenic therapy
is selected from the group consisting of axitinib, pazopanib,
sorafenib, sunitinib, everolimus, temsirolimus, bevacizumab,
interleukins, interferon-.alpha., peginterferon, nivolumab,
AMP-514, and atezolizumab.
2. The method of claim 1, wherein the cabozantinib is administered
as cabozantinib (S)-malate.
3. The method of any of claims 1-2, cabozantinib (S)-malate is
administered in an amount sufficient to achieve a median time to
peak plasma concentration (Tmax) of from approximately 2 to 5 hours
post-dose; and a Cmax of 200 to 500 ng/mL.
4. The method of any of claims 1-3, wherein the prior
antiangiogenic therapy is selected from the group consisting of
axitinib, pazopanib, sorafenib, sunitinib, everolimus,
temsirolimus, bevacizumab, nivolumab, AMP-514, and
atezolizumab.
5. The method of any of claims 1-4, wherein the prior
anti-angiogenic therapy is everolimus.
6. The method of any of claims 1-5, wherein cabozantinib (S)-malate
is administered as a tablet comprising cabozantinib (S)-malate,
microcrystalline cellulose, anhydrous lactose, hydroxypropyl
cellulose, croscarmellose sodium, colloidal silicon dioxide
magenisum stearate, and film coating comprising hypromellose,
titanium dioxide, triacetin, and iron oxide yellow.
7. The method of any of claims 1-6, wherein the cabozantinib
(S)-malate is administered as a tablet formulation comprising
approximately: 30-32 percent by weight of cabozantinib, (S)-malate
salt; 38-40 percent by weight of microcrystalline cellulose; 18-22
percent by weight of lactose; 2-4 percent by weight of
hydroxypropyl cellulose; 4-8 percent by weight of croscarmellose
sodium; 0.2-0.6 percent by weight of colloidal silicon dioxide;
0.5-1 percent by weight of magnesium stearate; and further
comprising: a film coating material comprising hypromellose,
titanium dioxide, triacetin, and iron oxide yellow.
8. The method of any of claims 1-7, wherein the cabozantinib
(S)-malate is administered as a tablet formulation comprising
approximately (% w/w): 31-32 percent by weight of cabozantinib,
(S)-malate salt; 39-40 percent by weight of microcrystalline
cellulose; 19-20 percent by weight of lactose; 2.5-3.5 percent by
weight of hydroxypropyl cellulose; 5.5-6.5 percent by weight of
croscarmellose sodium; 0.25-0.35 percent by weight of colloidal
silicon dioxide; 0.7-0.8 percent by weight of magnesium stearate;
and further comprising: 3.9-4.1 percent by weight of a film coating
material comprising hypromellose, titanium dioxide, triacetin, and
iron oxide yellow.
9. The method of any of claims 1-8, wherein cabozantinib (S)-malate
is administered as a tablet formulation containing 20, 40, or 60 mg
of cabozantinib.
10. The method of any of claims 1-9, wherein cabozantinib
(S)-malate is administered as a tablet formulation selected from
the group consisting of: TABLE-US-00057 Theoretical Quantity
(mg/unit dose) 20-mg 40-mg 60-mg Ingredient Tablet* Tablet* Tablet*
Cabozantinib (S)-malate 25.34 50.69 76.03 Microcrystalline
Cellulose, 31.08 62.16 93.24 PH-102 Lactose Anhydrous, 60M 15.54
31.07 46.61 Hydroxypropyl Cellulose, EXF 2.400 4.800 7.200
Croscarmellose Sodium 4.800 9.600 14.40 Colloidal Silicon Dioxide
0.2400 0.4800 0.7200 Magnesium Stearate 0.6000 1.200 1.800
(Non-Bovine) Opadry .RTM. Yellow (03K92254) 3.200 6.400 9.600 Total
tablet weight 83.20 166.4 249.6 *Free Base Equivalent (FBE)
11. The method of any of claims 1-10, wherein the cabozantinib
(S)-malate is administered once daily.
12. The method of any of claims 1-11, wherein the amount of
cabozantinib that is administered once daily is 60 mg.
13. The method of any of claims 1-12, wherein the amount of
cabozantinib (S)-malate is sufficient to achieve a median time to
peak plasma concentration (Tmax) from 3.2 to 3.8 hours post-dose;
and a mean Cmax of 310 to 350 ng/mL.
14. The method of any of claims 1-13, wherein the overall survival
of the patient is extended as compared to patients taking
everolimus.
15. The method of any of claims 1-14, wherein the objective
response rate of the patient is extended as compared to patients
taking everolimus.
16. The method of any of claims 1-15, wherein both the overall
survival and the objective response rate of the patient is extended
as compared to patients taking everolimus.
17. The method of any of claims 1-15 wherein an amount of
cabozantinib (S)-malate is sufficient to achieve one, two, three,
four, five, six, seven, or eight effects selected from the group
consisting of: a median time to peak plasma concentration (Tmax)
from 2 to 5 hours post-dose; a Cmax of 200 to 500 ng/mL; an
AUC.sub.0-24 of 2500 to 5200 ng*h/mL; an AUC.sub.0-t of 18,000 to
42,000 ng*h/mL; an AUC.sub.0-.infin. of 19,000 to 45,000 ng*h/mL;
an oral volume distribution (Vz/F) of 100 to 600 L; a terminal
half-life of 90 to 135 h; and a clearance at steady state (CL/F) of
0.7 to 3.9 L/h; wherein the cabozantinib (S)-malate is administered
as a tablet formulation comprising approximately (% w/w): 31-32
percent by weight of cabozantinib, (S)-malate salt; 39-40 percent
by weight of microcrystalline cellulose; 19-20 percent by weight of
lactose; 2.5-3.5 percent by weight of hydroxypropyl cellulose;
5.5-6.5 percent by weight of croscarmellose sodium; 0.25-0.35
percent by weight of colloidal silicon dioxide; 0.7-0.8 percent by
weight of magnesium stearate; and further comprising: 3.9-4.1
percent by weight of a film coating material comprising
hypromellose, titanium dioxide, triacetin, and iron oxide
yellow.
18. The method of 17, wherein cabozantinib (S)-malate is
administered as a tablet formulation containing 20, 40, or 60 mg of
cabozantinib.
19. The method of any of claims 1-18, wherein the cabozantinib
(S)-malate is administered in an amount sufficient to achieve one,
two, three, four, five, six, seven, or eight effects selected from
the group consisting of: a median time to peak plasma concentration
(Tmax) from 2 to 5 hours post-dose; a Cmax of 200 to 500 ng/mL; an
AUC.sub.0-24 of 2500 to 5200 ng*h/mL; an AUC.sub.0-t of 18,000 to
42,000 ng*h/mL; an AUC.sub.0-.infin. of 19,000 to 45,000 ng*h/mL;
an oral volume distribution (Vz/F) of 100 to 600 L; a terminal
half-life of 90 to 135 h; and a clearance at steady state (CL/F) of
0.7 to 3.9 L/h
20. The method of any of claims 1-19, wherein the cabozantinib
(S)-malate is administered in an amount sufficient to achieve one,
two, three, four, five, six, seven, or eight effects selected from
the group consisting of: a median time to peak plasma concentration
(Tmax) from 2.5 to 4.5 hours post-dose; a Cmax of 250 to 450 ng/mL;
an AUC.sub.0-24 of 3000 to 4700 ng*h/mL; an AUC.sub.0-t of 23,000
to 37,000 ng*h/mL; an AUC.sub.0-.infin. of 24,000 to 40,000
ng*h/mL; an oral volume distribution (Vz/F) of 150 to 550 L; a
terminal half-life of 100 to 125 h; and a clearance at steady state
(CL/F) of 1.2 to 3.2 L/h.
21. The method of any of claims 1-20, wherein the cabozantinib
(S)-malate is administered in an amount sufficient to achieve one,
two, three, four, five, six, seven, or eight effects selected from
the group consisting of: a median time to peak plasma concentration
(Tmax) from 3 to 4 hours post-dose; a Cmax of 300 to 400 ng/mL; an
AUC.sub.0-24 of 3500 to 4200 ng*h/mL; an AUC.sub.0-t of 28,000 to
32,000 ng*h/mL; an AUC.sub.0-.infin. of 29,000 to 35,000 ng*h/mL;
an oral volume distribution (Vz/F) of 200 to 500 L; a terminal
half-life of 110 to 115 h; and a clearance at steady state (CL/F)
of 1.2 to 3.2
22. The method of any of claims 1-21, wherein the cabozantinib
(S)-malate is administered in an amount sufficient to achieve one,
two, three, four, five, six, seven, or eight effects selected from
the group consisting of: a median time to peak plasma concentration
(Tmax) from 3.2 to 3.8 hours post-dose; a Cmax of 310 to 350 ng/mL;
an AUC.sub.0-24 of 3700 to 4000 ng*h/mL; an AUC.sub.0-1 of 29,000
to 30,000 ng*h/mL; an AUC.sub.0-.infin. of 30,000 to 33,000
ng*h/mL; an oral volume distribution (Vz/F) of 300 to 400 L; a
terminal half-life of 110 to 114 h; and a clearance at steady state
(CL/F) of 2 to 3.
23. A method of treating advanced renal cell carcinoma in human
patients who have received prior anti-angiogenic therapy,
comprising administering to the patient cabozantinib or a
pharmaceutically acceptable salt thereof, wherein the overall
survival of the patients are extended as compared to the median
overall survival of patients who have received prior
anti-angiogenic therapy, wherein the prior anti-angiogenic therapy
is selected from the group consisting of axitinib, pazopanib,
sorafenib, sunitinib, everolimus, temsirolimus, bevacizumab,
interleukins, interferon-.alpha., peginterferon, nivolumab,
AMP-514, and atezolizumab.
24. The method of claim 23, wherein the cabozanitinib is
administered as cabozantinib (S)-malate.
25. The method of any of claims 23-24, wherein the overall survival
is extended for patients taking cabozantinib (S)-malate as compared
to patients who have received axitinib, pazopanib, sorafenib,
sunitinib, everolimus, temsirolimus, bevacizumab, nivolumab,
AMP-514, and atezolizumab as the prior anti-angiogenic therapy.
26. The method of any of claims 23-25, wherein the overall survival
is extended for patients taking cabozantinib (S)-malate as compared
to patients who have received prior anti-angiogenic therapy.
27. The method of any of claims 23-26, wherein the patients are
selected from the group consisting of patients with favorable,
intermediate, and poor prognoses on the Memorial Sloan Kettering
Cancer Center (MSKCC) Risk Group, patients with bone metastases,
patients with visceral metastases, and patients with visceral and
bone metastases.
28. The method of any of claims 23-27, wherein one or both of
progression-free survival (PFS) and objective response rate are
also extended over patients who have received prior anti-angiogenic
therapy.
29. The method of any of claims 23-28 wherein the cabozantinib
(S)-malate is administered in an amount sufficient to achieve to
achieve a median time to peak plasma concentration (Tmax) from 3.2
to 3.8 hours post-dose; and a mean Cmax of 310 to 350 ng/mL;
wherein: the overall survival of the patient is extended as
compared to a the median overall survival of patients taking who
have received prior anti-angiogenic therapy; and wherein one or
both of progression-free survival (PFS) and objective response rate
are also extended over patients taking who have received prior
anti-angiogenic therapy.
30. The method of any of claims 23-29, wherein the prior
antiangiogenic therapy is selected from the group consisting of
axitinib, pazopanib, sorafenib, sunitinib, and everolimus.
31. The method of any of claims 23-30, wherein the prior
anti-angiogenic therapy is everolimus.
32. The method of any of claims 23-31, wherein cabozantinib
(S)-malate is administered as a tablet comprising cabozantinib
(S)-malate, microcrystalline cellulose, anhydrous lactose,
hydroxypropyl cellulose, croscarmellose sodium, colloidal silicon
dioxide magenisum stearate, and film coating comprising
hypromellose, titanium dioxide, triacetin, and iron oxide
yellow.
33. The method of any of claims 23-32, wherein the cabozantinib
(S)-malate is administered as a tablet formulation comprising
approximately: 30-32 percent by weight of cabozantinib, (S)-malate
salt; 38-40 percent by weight of microcrystalline cellulose; 18-22
percent by weight of lactose; 2-4 percent by weight of
hydroxypropyl cellulose; 4-8 percent by weight of croscarmellose
sodium; 0.2-0.6 percent by weight of colloidal silicon dioxide;
0.5-1 percent by weight of magnesium stearate; and further
comprising: a film coating material comprising hypromellose,
titanium dioxide, triacetin, and iron oxide yellow.
34. The method of any of claims 23-33, wherein the cabozantinib
(S)-malate is administered as a tablet formulation comprising
approximately (% w/w): 31-32 percent by weight of cabozantinib,
(S)-malate salt; 39-40 percent by weight of microcrystalline
cellulose; 19-20 percent by weight of lactose; 2.5-3.5 percent by
weight of hydroxypropyl cellulose; 5.5-6.5 percent by weight of
croscarmellose sodium; 0.25-0.35 percent by weight of colloidal
silicon dioxide; 0.7-0.8 percent by weight of magnesium stearate;
and further comprising: 3.9-4.1 percent by weight of a film coating
material comprising hypromellose, titanium dioxide, triacetin, and
iron oxide yellow.
35. The method of any of claims 23-34, wherein cabozantinib
(S)-malate is administered as a tablet formulation containing 20,
40, or 60 mg of cabozantinib.
36. The method of any of claims 23-35, wherein cabozantinib
(S)-malate is administered as a tablet formulation selected from
the group consisting of: TABLE-US-00058 Theoretical Quantity
(mg/unit dose) 20-mg 40-mg 60-mg Ingredient Tablet* Tablet* Tablet*
Cabozantinib (S)-malate 25.34 50.69 76.03 Microcrystalline
Cellulose, 31.08 62.16 93.24 PH-102 Lactose Anhydrous, 60M 15.54
31.07 46.61 Hydroxypropyl Cellulose, EXF 2.400 4.800 7.200
Croscarmellose Sodium 4.800 9.600 14.40 Colloidal Silicon Dioxide
0.2400 0.4800 0.7200 Magnesium Stearate 0.6000 1.200 1.800
(Non-Bovine) Opadry .RTM. Yellow (03K92254) 3.200 6.400 9.600 Total
tablet weight 83.20 166.4 249.6 *Free Base Equivalent (FBE)
37. The method of any of claims 23-36, wherein the cabozantinib
(S)-malate is administered once daily.
38. The method of any of claims 23-37, wherein the amount of
cabozantinib that is administered once daily is 60 mg.
39. The method of any of claims 23-38, wherein the amount of
cabozantinib (S)-malate is sufficient to achieve a median time to
peak plasma concentration (Tmax) of from 3.2 to 3.8 hours post-dose
and a mean Cmax of 310 to 350 ng/mL.
40. The method of any of claims 23-39, wherein the overall survival
of the patient are extended as compared to the median overall
survival of patients taking everolimus; and wherein the
progression-free survival of the patient is extended over patients
taking everolimus.
41. The method of any of claims 23-40, wherein the overall survival
of patients is extended as compared to the median overall survival
of patients taking everolimus; and wherein the objective response
rate is extended over patients taking everolimus.
42. The method of any of claims 23-41, wherein the overall survival
of patients is extended as compared to everolimus and both of
progression-free survival (PFS) and objective response rate are
also extended as compared to patients taking everolimus.
43. A method of treating renal cell carcinoma in a human patient
who has received prior anti-angiogenic therapy, comprising
administering to the patient an amount of cabozantinib (S)-malate
sufficient to achieve one, two, three, four, five, six, seven, or
eight effects selected from the group consisting of: a median time
to peak plasma concentration (Tmax) from 2 to 5 hours post-dose; a
Cmax of 200 to 500 ng/mL; an AUC.sub.0-24 of 2500 to 5200 ng*h/mL;
an AUC.sub.0-t of 18,000 to 42,000 ng*h/mL; an AUC.sub.0-.infin. of
19,000 to 45,000 ng*h/mL; an oral volume distribution (Vz/F) of 100
to 600 L; a terminal half-life of 90 to 135 h; and a clearance at
steady state (CL/F) of 0.7 to 3.9 L/h; wherein: the cabozantinib
(S)-malate is administered as a tablet formulation comprising
approximately (% w/w): 31-32 percent by weight of cabozantinib,
(S)-malate salt; 39-40 percent by weight of microcrystalline
cellulose; 19-20 percent by weight of lactose; 2.5-3.5 percent by
weight of hydroxypropyl cellulose; 5.5-6.5 percent by weight of
croscarmellose sodium; 0.25-0.35 percent by weight of colloidal
silicon dioxide; 0.7-0.8 percent by weight of magnesium stearate;
and further comprising: 3.9-4.1 percent by weight of a film coating
material comprising hypromellose, titanium dioxide, triacetin, and
iron oxide yellow.
44. The method of 43, wherein cabozantinib (S)-malate is
administered as a tablet formulation containing 20, 40, or 60 mg of
cabozantinib.
45. The method of any of claims 43-44, wherein cabozantinib
(S)-malate is administered as a tablet formulation selected from
the group consisting of: TABLE-US-00059 Theoretical Quantity
(mg/unit dose) 20-mg 40-mg 60-mg Ingredient Tablet* Tablet* Tablet*
Cabozantinib (S)-malate 25.34 50.69 76.03 Microcrystalline
Cellulose, 31.08 62.16 93.24 PH-102 Lactose Anhydrous, 60M 15.54
31.07 46.61 Hydroxypropyl Cellulose, EXF 2.400 4.800 7.200
Croscarmellose Sodium 4.800 9.600 14.40 Colloidal Silicon Dioxide
0.2400 0.4800 0.7200 Magnesium Stearate 0.6000 1.200 1.800
(Non-Bovine) Opadry .RTM. Yellow (03K92254) 3.200 6.400 9.600 Total
tablet weight 83.20 166.4 249.6 *Free Base Equivalent (FBE)
46. The method of any of claims 43-45, wherein the cabozantinib
(S)-malate is administered in an amount sufficient to achieve one,
two, three, four, five, six, seven, or eight effects selected from
the group consisting of: a median time to peak plasma concentration
(Tmax) from 2 to 5 hours post-dose; a Cmax of 200 to 500 ng/mL; an
AUC.sub.0-24 of 2500 to 5200 ng*h/mL; an AUC.sub.0-t of 18,000 to
42,000 ng*h/mL; an AUC.sub.0-.infin. of 19,000 to 45,000 ng*h/mL;
an oral volume distribution (Vz/F) of 100 to 600 L; a terminal
half-life of 90 to 135 h; and a clearance at steady state (CL/F) of
0.7 to 3.9 L/h
47. The method of any of claims 43-46, wherein the cabozantinib
(S)-malate is administered in an amount sufficient to achieve one,
two, three, four, five, six, seven, or eight effects selected from
the group consisting of: a median time to peak plasma concentration
(Tmax) from 2.5 to 4.5 hours post-dose; a Cmax of 250 to 450 ng/mL;
an AUC.sub.0-24 of 3000 to 4700 ng*h/mL; an AUC.sub.0-t of 23,000
to 37,000 ng*h/mL; an AUC.sub.0-.infin. of 24,000 to 40,000
ng*h/mL; an oral volume distribution (Vz/F) of 150 to 550 L; a
terminal half-life of 100 to 125 h; and a clearance at steady state
(CL/F) of 1.2 to 3.2 L/h.
48. The method of any of claims 43-47, wherein the cabozantinib
(S)-malate is administered in an amount sufficient to achieve one,
two, three, four, five, six, seven, or eight effects selected from
the group consisting of: a median time to peak plasma concentration
(Tmax) from 3 to 4 hours post-dose; a Cmax of 300 to 400 ng/mL; an
AUC.sub.0-24 of 3500 to 4200 ng*h/mL; an AUC.sub.0-t of 28,000 to
32,000 ng*h/mL; an AUC.sub.0-.infin. of 29,000 to 35,000 ng*h/mL;
an oral volume distribution (Vz/F) of 200 to 500 L; a terminal
half-life of 110 to 115 h; and a clearance at steady state (CL/F)
of 1.2 to 3.2
49. The method of any of claims 43-48, wherein the cabozantinib
(S)-malate is administered in an amount sufficient to achieve one,
two, three, four, five, six, seven, or eight effects selected from
the group consisting of: a median time to peak plasma concentration
(Tmax) from 3.2 to 3.8 hours post-dose; a Cmax of 310 to 350 ng/mL;
an AUC.sub.0-24 of 3700 to 4000 ng*h/mL; an AUC.sub.0-t of 29,000
to 30,000 ng*h/mL; an AUC.sub.0-.infin. of 30,000 to 33,000
ng*h/mL; an oral volume distribution (Vz/F) of 300 to 400 L; a
terminal half-life of 110 to 114 h; and a clearance at steady state
(CL/F) of 2 to 3.
50. The method of any of claims 43-49, wherein the overall survival
of the patient is extended as compared to the median overall
survival of patients taking everolimus; and wherein the
progression-free survival of the patient is extended over patients
taking everolimus.
51. The method of any of claims 43-50, wherein the overall survival
of the patient is extended as compared to the median overall
survival of patients taking everolimus; and wherein the objective
response rate is extended over patients taking everolimus.
52. The method of any of claims 43-51, wherein the overall survival
of the patient is extended as compared to a the median overall
survival of patients taking everolimus; and wherein
progression-free survival (PFS) and objective response rate are
also extended over patients taking everolimus.
54. A method of treating advanced renal cell carcinoma in patients
in need of such treatment who has received prior antiangiogenic
therapy selected from the group consisting of sunitinib therapy,
pazopanib therapy, and anti-PD-1/PD-L1 immune checkpoint inhibitor
therapy, comprising administering cabozantinib ##STR00006## or a
pharmaceutically acceptable salt thereof.
55. The method of claim 54, wherein cabozantinib is administered as
cabozantinib S-malate salt. measuring plasma clearance (CL/F) and
apparent volume of distribution of the central compartment
(V.sub.c/F) from a patient; utilizing the measured plasma clearance
(CL/F) and apparent volume of distribution of the central
compartment (V.sub.c/F) to calculate the responsiveness of the
patient to the administered composition comprising said TKI
inhibitor; and comparing the calculated responsiveness to a
predetermined responsiveness to compositions comprising said TKI
inhibitor.
63. The method of 62, wherein the TKI inhibitor is cabozantinb.
64. A method for treating renal cell carcinoma, comprising
administering as a starting dose 60 mg of cabozantinib free base
equivalent thereof to a patient in need of such treatment, wherein
progression free survival is extended, tumor growth is reduced, and
overall response rate is extended as compared to 40 mg or 20 mg
starting doses or cabozantinib free base equivalent.
65. The method of claim 64, wherein cabozantinib is administered as
cabozantinib S-malate salt.
66. A method of treating renal cell carcinoma in a human patient,
wherein the method comprises administering cabozantinib or a
pharmaceutically acceptable salt thereof daily in an amount of 60
mg of cabozantinib free base equivalent.
67. The method of claim 66, wherein the renal cell carcinoma is
advanced renal cell carcinoma.
68. The method of any of claims 66-67, wherein the patient is an
adult patient.
69. The method of any of claims 66-68, wherein said amount is
administered to the patient once daily.
70. The method of any of claims 66-69, wherein the cabozantinib is
administered as cabozantinib (S)-malate.
71. The method of any of claims 66-70, wherein cabozantinib
(S)-malate is administered as a tablet comprising cabozantinib
(S)-malate, microcrystalline cellulose, anhydrous lactose,
hydroxypropyl cellulose, croscarmellose sodium, colloidal silicon
dioxide magenisum
56. The method of any of claims 54-55, wherein the median
progression free survival is at least 9.1 months when the prior
antiangiogenic therapy is sunitinib therapy only and at least 7.4
months when the prior antiangiogenic therapy is pazopanib only.
57. The method of any of claims 54-56, wherein the median overall
survival is at least 21.4 months when the prior antiangiogenic
therapy was sunitinib only and at least 22.0 months when the prior
antiangiogenic therapy was pazopanib only.
58. The method of any of claims 54-57, wherein the median
progression free survival is at least 9.1 months when the prior
antiangiogenic therapy is sunitinib therapy only and at least 7.4
months when the prior antiangiogenic therapy was pazopanib only and
the median overall survival is at least 21.4 months when the prior
antiangiogenic therapy was sunitinib only and at least 22.0 months
when the prior antiangiogenic therapy was pazopanib only.
59. A method of optimizing the treatment of a renal carcinoma
patient with a tyrosine kinase inhibitor (TKI) comprising the step
of quantifying the patient's response to one or more dosing
regimens of said TKI inhibitor with a model employing Equation 1:
dY dt = k grow Y - ( k dmax + k dmax tol e - k tol t ) Cavg ( EC 50
+ Cavg ) Y Equation .times. .times. 1 ##EQU00004## where: dY/dt is
the change in tumor diameter per unit time k.sub.grow is the
first-order growth rate constant k.sub.dmax is the maximum
non-attenuating drug induced tumor decay rate k.sub.dmax_tol is the
maximum loss in the decay rate due to resistance k.sub.tol is the
rate constant which governs the rate of attenuation EC.sub.50 is
the cabozantinib concentration yielding one-half of the current
tumor decay rate Cavg is the individual predicted daily average
cabozantinib concentration.
60. The method of 59, wherein the target of the TKI is selected
from the group consisting of VEGF receptors, MET, and AXL.
61. The method of any of claims 59-60, wherein the TKI inhibitor is
cabozantinib.
62. A method of adjusting the dosing level of a composition
comprising a tyrosine kinase (TKI) inhibitor for administration to
a patient, the method comprising: stearate, and film coating
comprising hypromellose, titanium dioxide, triacetin, and iron
oxide yellow.
72. The method of any of claims 66-71, wherein the cabozantinib
(S)-malate is administered as a tablet formulation comprising
approximately: 30-32 percent by weight of cabozantinib, (S)-malate
salt; 38-40 percent by weight of microcrystalline cellulose; 18-22
percent by weight of lactose; 2-4 percent by weight of
hydroxypropyl cellulose; 4-8 percent by weight of croscarmellose
sodium; 0.2-0.6 percent by weight of colloidal silicon dioxide;
0.5-1 percent by weight of magnesium stearate; and further
comprising: a film coating material comprising hypromellose,
titanium dioxide, triacetin, and iron oxide yellow.
73. The method of any of claims 66-72, wherein the cabozantinib
(S)-malate is administered as a tablet formulation comprising
approximately (% w/w): 31-32 percent by weight of cabozantinib,
(S)-malate salt; 39-40 percent by weight of microcrystalline
cellulose; 19-20 percent by weight of lactose; 2.5-3.5 percent by
weight of hydroxypropyl cellulose; 5.5-6.5 percent by weight of
croscarmellose sodium; 0.25-0.35 percent by weight of colloidal
silicon dioxide; 0.7-0.8 percent by weight of magnesium stearate;
and further comprising: 3.9-4.1 percent by weight of a film coating
material comprising hypromellose, titanium dioxide, triacetin, and
iron oxide yellow.
74. The method of any of claims 66-73, wherein the starting dose of
60 mg cabozantinib free base equivalent can be reduced to 40 or 20
mg cabozantinib free base equivalent to minimize adverse side
effects.
75. The method of any of claims 66-74, wherein cabozantinib
(S)-malate is administered as a tablet formulation selected from
the group consisting of: TABLE-US-00060 Theoretical Quantity
(mg/unit dose) 20-mg 40-mg 60-mg Ingredient Tablet* Tablet* Tablet*
Cabozantinib (S)-malate 25.34 50.69 76.03 Microcrystalline
Cellulose, 31.08 62.16 93.24 PH-102 Lactose Anhydrous, 60M 15.54
31.07 46.61 Hydroxypropyl Cellulose, EXF 2.400 4.800 7.200
Croscarmellose Sodium 4.800 9.600 14.40 Colloidal Silicon Dioxide
0.2400 0.4800 0.7200 Magnesium Stearate 0.6000 1.200 1.800
(Non-Bovine) Opadry .RTM. Yellow (03K92254) 3.200 6.400 9.600 Total
tablet weight 83.20 166.4 249.6 *Free Base Equivalent (FBE)
76. The method of any of claims 66-75, wherein the patient has
received prior anti-angiogenic therapy.
77. The method of claims 66-76, wherein the prior anti-angiogenic
therapy is selected axitinib, pazopanib, sorafenib, sunitinib,
everolimus, temsirolimus, bevacizumab, interleukins,
interferon-.alpha., peginterferon, nivolumab, AMP-514, and
atezolizumab.
78. The method of claims 66-77, wherein the prior anti-angiogenic
therapy is everolimus therapy.
79. A method of treating renal cell carcinoma in a human patient,
wherein the method comprises administering cabozantinib or a
pharmaceutically acceptable salt thereof daily in an amount of 40
mg of cabozantinib free base equivalent.
80. The method of claim 79, wherein the renal cell carcinoma is
advanced renal cell carcinoma.
81. The method of any of claims 79-80, wherein the patient is an
adult patient.
82. The method of any of claims 79-81, wherein said amount is
administered to the patient once daily.
83. The method of any of claims 79-82, wherein the cabozantinib is
administered as cabozantinib (S)-malate.
84. The method of any of claims 79-83, wherein cabozantinib
(S)-malate is administered as a tablet comprising cabozantinib
(S)-malate, microcrystalline cellulose, anhydrous lactose,
hydroxypropyl cellulose, croscarmellose sodium, colloidal silicon
dioxide magenisum stearate, and film coating comprising
hypromellose, titanium dioxide, triacetin, and iron oxide
yellow.
85. The method of any of claims 79-84, wherein the cabozantinib
(S)-malate is administered as a tablet formulation comprising
approximately: 30-32 percent by weight of cabozantinib, (S)-malate
salt; 38-40 percent by weight of microcrystalline cellulose; 18-22
percent by weight of lactose; 2-4 percent by weight of
hydroxypropyl cellulose; 4-8 percent by weight of croscarmellose
sodium; 0.2-0.6 percent by weight of colloidal silicon dioxide;
0.5-1 percent by weight of magnesium stearate; and further
comprising: a film coating material comprising hypromellose,
titanium dioxide, triacetin, and iron oxide yellow.
86. The method of any of claims 79-85, wherein the cabozantinib
(S)-malate is administered as a tablet formulation comprising
approximately (% w/w): 31-32 percent by weight of cabozantinib,
(S)-malate salt; 39-40 percent by weight of microcrystalline
cellulose; 19-20 percent by weight of lactose; 2.5-3.5 percent by
weight of hydroxypropyl cellulose; 5.5-6.5 percent by weight of
croscarmellose sodium; 0.25-0.35 percent by weight of colloidal
silicon dioxide; 0.7-0.8 percent by weight of magnesium stearate;
and further comprising: 3.9-4.1 percent by weight of a film coating
material comprising hypromellose, titanium dioxide, triacetin, and
iron oxide yellow.
87. The method of any of claims 79-86, wherein cabozantinib
(S)-malate is administered as a tablet formulation selected from
the group consisting of: TABLE-US-00061 Theoretical Quantity
(mg/unit dose) 20-mg 40-mg 60-mg Ingredient Tablet* Tablet* Tablet*
Cabozantinib (S)-malate 25.34 50.69 76.03 Microcrystalline
Cellulose, 31.08 62.16 93.24 PH-102 Lactose Anhydrous, 60M 15.54
31.07 46.61 Hydroxypropyl Cellulose, EXF 2.400 4.800 7.200
Croscarmellose Sodium 4.800 9.600 14.40 Colloidal Silicon Dioxide
0.2400 0.4800 0.7200 Magnesium Stearate 0.6000 1.200 1.800
(Non-Bovine) Opadry .RTM. Yellow (03K92254) 3.200 6.400 9.600 Total
tablet weight 83.20 166.4 249.6 *Free Base Equivalent (FBE)
88. The method of any of claims 79-87, wherein the patient has
received prior anti-angiogenic therapy.
89. The method of claims 79-88, wherein the prior anti-angiogenic
therapy is selected axitinib, pazopanib, sorafenib, sunitinib,
everolimus, temsirolimus, bevacizumab, interleukins,
interferon-.alpha., peginterferon, nivolumab, AMP-514, and
atezolizumab.
90. The method of claims 79-89, wherein the prior anti-angiogenic
therapy is everolimus therapy.
91. A method of treating renal cell carcinoma in a human patient,
wherein the method comprises administering cabozantinib or a
pharmaceutically acceptable salt thereof daily in an amount of 20
mg of cabozantinib free base equivalent.
92. The method of claim 91, wherein the renal cell carcinoma is
advanced renal cell carcinoma.
93. The method of any of claims 91-92, wherein the patient is an
adult patient.
94. The method of any of claims 91-93, wherein said amount is
administered to the patient once daily.
95. The method of any of claims 91-94, wherein the cabozantinib is
administered as cabozantinib (S)-malate.
96. The method of any of claims 91-95, wherein cabozantinib
(S)-malate is administered as a tablet comprising cabozantinib
(S)-malate, microcrystalline cellulose, anhydrous lactose,
hydroxypropyl cellulose, croscarmellose sodium, colloidal silicon
dioxide magenisum stearate, and film coating comprising
hypromellose, titanium dioxide, triacetin, and iron oxide
yellow.
97. The method of any of claims 91-96, wherein the cabozantinib
(S)-malate is administered as a tablet formulation comprising
approximately: 30-32 percent by weight of cabozantinib, (S)-malate
salt; 38-40 percent by weight of microcrystalline cellulose; 18-22
percent by weight of lactose; 2-4 percent by weight of
hydroxypropyl cellulose; 4-8 percent by weight of croscarmellose
sodium; 0.2-0.6 percent by weight of colloidal silicon dioxide;
0.5-1 percent by weight of magnesium stearate; and further
comprising: a film coating material comprising hypromellose,
titanium dioxide, triacetin, and iron oxide yellow.
98. The method of any of claims 91-97, wherein the cabozantinib
(S)-malate is administered as a tablet formulation comprising
approximately (% w/w): 31-32 percent by weight of cabozantinib,
(S)-malate salt; 39-40 percent by weight of microcrystalline
cellulose; 19-20 percent by weight of lactose; 2.5-3.5 percent by
weight of hydroxypropyl cellulose; 5.5-6.5 percent by weight of
croscarmellose sodium; 0.25-0.35 percent by weight of colloidal
silicon dioxide; 0.7-0.8 percent by weight of magnesium stearate;
and further comprising: 3.9-4.1 percent by weight of a film coating
material comprising hypromellose, titanium dioxide, triacetin, and
iron oxide yellow.
99. The method of any of claims 91-98, wherein cabozantinib
(S)-malate is administered as a tablet formulation selected from
the group consisting of: TABLE-US-00062 Theoretical Quantity
(mg/unit dose) 20-mg 40-mg 60-mg Ingredient Tablet* Tablet* Tablet*
Cabozantinib (S)-malate 25.34 50.69 76.03 Microcrystalline
Cellulose, 31.08 62.16 93.24 PH-102 Lactose Anhydrous, 60M 15.54
31.07 46.61 Hydroxypropyl Cellulose, EXF 2.400 4.800 7.200
Croscarmellose Sodium 4.800 9.600 14.40 Colloidal Silicon Dioxide
0.2400 0.4800 0.7200 Magnesium Stearate 0.6000 1.200 1.800
(Non-Bovine) Opadry .RTM. Yellow (03K92254) 3.200 6.400 9.600 Total
tablet weight 83.20 166.4 249.6 *Free Base Equivalent (FBE)
100. The method of any of claims 91-99, wherein the patient has
received prior anti-angiogenic therapy.
101. The method of claims 91-100, wherein the prior anti-angiogenic
therapy is selected axitinib, pazopanib, sorafenib, sunitinib,
everolimus, temsirolimus, bevacizumab, interleukins,
interferon-.alpha., peginterferon, nivolumab, AMP-514, and
atezolizumab.
102. The method of claims 91-101, wherein the prior anti-angiogenic
therapy is everolimus therapy.
Description
RELATED APPLICATIONS
[0001] This application claims priority to U.S. Application Ser.
No. 62/323,536, filed Apr. 15, 2016, U.S. Application Ser. No.
62/323,548, filed Apr. 15, 2016, U.S. Application Ser. No.
62/323,556, filed Apr. 15, 2016, U.S. Application Ser. No.
62/324,157, filed Apr. 18, 2016, U.S. Application Ser. No.
62/324,158, filed Apr. 18, 2016, U.S. Application Ser. No.
62/324,176, filed Apr. 18, 2016, U.S. Application Ser. No.
62/338,154, filed May 18, 2016, U.S. Application Ser. No.
62/338,195, filed May 18, 2016, U.S. Application Ser. No.
62/338,240, filed May 18, 2016, U.S. Application Ser. No.
62/338,267, filed May 18, 2016, U.S. Application Ser. No.
62/345,652, filed Jun. 3, 2016, U.S. Application Ser. No.
62/400,481, filed Sep. 27, 2016, U.S. Application Ser. No.
62/457,471, filed Feb. 10, 2017, U.S. Application Ser. No.
62/457,613, filed Feb. 10, 2017, and U.S. Application Ser. No.
62/457,671, filed Feb. 10, 2017. The entire contents of the
aforementioned applications are incorporated herein by
reference.
TECHNICAL FIELD
[0002] The present disclosure relates to methods of treating renal
cell carcinoma (RCC) in human patients who have received prior
anti-angiogenic therapy. The method employs cabozantinib, a kinase
inhibitor.
BACKGROUND
[0003] Advances in the understanding of the molecular pathology of
renal cell carcinoma (RCC) have led to the development of agents
targeting the vascular endothelial growth receptor (VEGFR) and mTOR
signaling pathways. Commonly used first-line therapies in patients
with advanced RCC are the VEGFR tyrosine kinase inhibitors (TKIs)
sunitinib and pazopanib. Second-line therapies include the VEGFR
TKIs axitinib and sorafenib, the mTOR inhibitor everolimus, and the
programmed cell death receptor 1 (PD-1) checkpoint inhibitor
nivolumab. Motzer R J, Jonasch E, Agarwal N, et al. Kidney cancer,
version 3. 2015. J Natl Compr Canc Netw 2015; 13: 151-9. Powles T,
Staehler M, Ljungberg B, et al. Updated EAU Guidelines for Clear
Cell Renal Cancer Patients Who Fail VEGF Targeted Therapy. Eur Urol
2016; 69: 4-6. Motzer R J, Escudier B, McDermott D F, et al.
Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N
Engl J Med 2015; 373: 1803-13. Despite a number of available
therapies, few have shown a survival benefit, and no agent has
demonstrated an improvement in all three efficacy endpoints of
progression-free survival (PFS), objective response rate, and
overall survival in a randomized phase 3 trial compared to standard
therapy in previously-treated RCC patients.
[0004] As a result, a need remains for improved therapies for the
treatment of renal cell carcinoma and, in particular, therapies
that achieve improvement in the three efficacy endpoints of
progression-free survival (PFS), objective response rate, and
overall survival in the treatment of renal cell carcinoma.
SUMMARY
[0005] These and other needs are met by the present invention,
which is directed to a method of treating advanced renal cell
carcinoma (RCC) in human patients who have received prior
anti-angiogenic therapy. The method employs cabozantinib. The
invention is also directed to the use of cabozantinib for treating
advanced renal cell carcinoma (RCC) in human patients who have
received prior anti-angiogenic therapy. The invention is also
directed to the use of cabozantinib in the manufacture of a
medicament for treating advanced renal cell carcinoma (RCC) in
human patients who have received prior anti-angiogenic therapy.
[0006] The methods and associated uses disclosed herein employ
cabozantinib, which is an oral inhibitor of tyrosine kinases
including MET, VEGF receptors, and AXL. Cabozantinib has the
structure depicted below.
##STR00001##
[0007] In preferred embodiments, the (S)-malate salt of
cabozantinib is administered. Cabozantinib (S)-malate is described
chemically as
N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N'-(4-fluorophenyl)cyclopropa-
ne-1,1-dicarboxamide, (2S)-hydroxybutanedioate. The molecular
formula is C.sub.28H.sub.24FN.sub.3O.sub.5.C.sub.4H.sub.6O.sub.5,
and the molecular weight is 635.6 Daltons as malate salt. The
chemical structure of cabozantinib (S)-malate salt is depicted
below.
##STR00002##
Cabozantinib as a capsule formulation (COMETRIQ.RTM.) has been
approved for the treatment of medullary thyroid cancer.
[0008] In preferred embodiments, the cabozantinib is administered
as CABOMETYX.RTM., which is a tablet formulation of the (S)-malate
salt of cabozantinib. The tablet formulation (CABOMETYX.RTM.)
achieved a 19% increase in the Cmx compared to the capsule
formulation (COMETRIQ.RTM.) following a single 140 mg dose. A less
than 10% difference in the AUC was observed between cabozantinib
tablet (CABOMETYX.RTM.) and capsule (COMETRIQ.RTM.) formulations.
Importantly, CABOMETYX.RTM. is the first agent to demonstrate an
improvement in all three efficacy endpoints of progression-free
survival (PFS), objective response rate, and overall survival in a
late stage clinical trial for treating advanced renal cell
carcinoma (RCC) who have received prior anti-angiogenic therapy, as
described in U.S. Ser. No. 62/323,536 filed Apr. 15, 2016, the
entire contents of which is incorporated herein by reference.
[0009] Thus, in one aspect, the invention is directed to a method
of treating advanced renal cell carcinoma with or without bone
metastases in a human patient who has received prior
anti-angiogenic therapy comprising administering to the patient an
amount of cabozantinib or a pharmaceutically acceptable salt
thereof, wherein progression-free survival (PFS), and one or both
of overall survival (OS) and objective response rate (ORR) are
extended as compared to patients who have received prior
anti-angiogenic therapy. In preferred embodiments of this and other
aspects, cabozantinib is administered as cabozantinib
(S)-malate.
[0010] In another aspect, the invention is directed to a method of
treating renal cell carcinoma that has metastasized to bone in a
human patient who has received prior anti-angiogenic therapy
comprising administering to the patient an amount of cabozantinib
or a pharmaceutically acceptable salt thereof, wherein
progression-free survival (PFS), and one or both of overall
survival (OS) and objective response rate (ORR) are extended as
compared to patients who have received prior anti-angiogenic
therapy. In preferred embodiments of this and other aspects,
cabozantinib is administered as cabozantinib (S)-malate.
[0011] In another aspect, the invention is directed to a method of
treating advanced renal cell carcinoma in a human patient who has
received prior anti-angiogenic therapy comprising administering to
the patient an amount of cabozantinib (S)-malate sufficient to
achieve one or more effects selected from the group consisting of a
median time to peak plasma concentration (Tmax) of from
approximately 3.2 to 3.8 hours post-dose; and a Cmax of 310 to 350
ng/mL, wherein the median overall survival of the patients are
extended as compared to the median overall survival of patients who
have received prior anti-angiogenic therapy.
[0012] In another aspect, the invention is directed to a method of
treating advanced renal cell carcinoma in human patients in need of
such treatment who have received prior everolimus therapy,
comprising administering to the patients an amount of cabozantinib
(S)-malate free base equivalent (FBE) sufficient to achieve one,
two, three, four, or five effects selected from the group
consisting of:
[0013] a Cmax of 30 to 500 ng/mL;
[0014] an AUC.sub.0-24 of 500 to 5200 ng*h/mL;
[0015] an AUC.sub.0-t of 4500 to 42,000 ng*h/mL;
[0016] an AUC.sub.0-.infin. of 5000 to 45,000 ng*h/mL;
[0017] a terminal half-life of 90 to 165 h;
[0018] wherein the cabozantinib (S)-malate is administered as a
tablet formulation comprising approximately (% w/w):
[0019] 31-32 percent by weight of cabozantinib, (S)-malate
salt;
[0020] 39-40 percent by weight of microcrystalline cellulose;
[0021] 19-20 percent by weight of lactose;
[0022] 2.5-3.5 percent by weight of hydroxypropyl cellulose;
[0023] 5.5-6.5 percent by weight of croscarmellose sodium;
[0024] 0.25-0.35 percent by weight of colloidal silicon
dioxide;
[0025] 0.7-0.8 percent by weight of magnesium stearate; and further
comprising:
[0026] 3.9-4.1 percent by weight of a film coating material
comprising hypromellose, titanium dioxide, triacetin, and iron
oxide yellow; and wherein:
[0027] the median overall survival of the patients is extended as
compared to the median overall survival of patients taking
everolimus; and wherein
[0028] one or both of progression-free survival (PFS) and objective
response rate are also extended as compared to patients taking
everolimus.
[0029] In another aspect, the invention is directed to a method of
treating advanced renal cell carcinoma in human patients in need of
such treatment who have received prior everolimus therapy,
comprising administering to the patients 20 mg, 40 mg, or 60 mg of
cabozantinib (S)-malate free base equivalent (FBE) sufficient to
achieve one, two, three, four, or five effects selected from the
group consisting of:
[0030] a Cmax of 30 to 500 ng/mL;
[0031] an AUC.sub.0-24 of 500 to 5200 ng*h/mL;
[0032] an AUC.sub.0-t of 4500 to 42,000 ng*h/mL;
[0033] an AUC.sub.0-.infin. of 5000 to 45,000 ng*h/mL;
[0034] a terminal half-life of 90 to 165 h;
[0035] wherein the cabozantinib (S)-malate is administered as a
tablet formulation comprising approximately (% w/w):
[0036] 31-32 percent by weight of cabozantinib, (S)-malate
salt;
[0037] 39-40 percent by weight of microcrystalline cellulose;
[0038] 19-20 percent by weight of lactose;
[0039] 2.5-3.5 percent by weight of hydroxypropyl cellulose;
[0040] 5.5-6.5 percent by weight of croscarmellose sodium;
[0041] 0.25-0.35 percent by weight of colloidal silicon
dioxide;
[0042] 0.7-0.8 percent by weight of magnesium stearate; and further
comprising:
[0043] 3.9-4.1 percent by weight of a film coating material
comprising hypromellose, titanium dioxide, triacetin, and iron
oxide yellow; and wherein:
[0044] the median overall survival of the patients is extended as
compared to the median overall survival of patients taking
everolimus; and wherein
[0045] one or both of progression-free survival (PFS) and objective
response rate are also extended as compared to patients taking
everolimus.
[0046] In another aspect, the invention is directed to a method of
treating advanced renal cell carcinoma in human patients in need of
such treatment who have received prior everolimus therapy,
comprising administering to the patients an amount of cabozantinib
(S)-malate free base equivalent (FBE) sufficient to achieve one,
two, three, four, five, six, seven, or eight effects selected from
the group consisting of:
[0047] a median time to peak plasma concentration (Tmax) from 2 to
5 hours post-dose;
[0048] a Cmax of 200 to 500 ng/mL;
[0049] an AUC.sub.0-24 of 2500 to 5200 ng*h/mL;
[0050] an AUC.sub.0-t of 18,000 to 42,000 ng*h/mL;
[0051] an AUC.sub.0-.infin. of 19,000 to 45,000 ng*h/mL;
[0052] an oral volume distribution (Vz/F) of 100 to 600 L;
[0053] a terminal half-life of 90 to 135 h; and
[0054] a clearance at steady state (CL/F) of 0.7 to 3.9 L/h;
wherein:
[0055] the cabozantinib (S)-malate is administered as a tablet
formulation comprising approximately (% w/w):
[0056] 31-32 percent by weight of cabozantinib, (S)-malate
salt;
[0057] 39-40 percent by weight of microcrystalline cellulose;
[0058] 19-20 percent by weight of lactose;
[0059] 2.5-3.5 percent by weight of hydroxypropyl cellulose;
[0060] 5.5-6.5 percent by weight of croscarmellose sodium;
[0061] 0.25-0.35 percent by weight of colloidal silicon
dioxide;
[0062] 0.7-0.8 percent by weight of magnesium stearate; and further
comprising:
[0063] 3.9-4.1 percent by weight of a film coating material
comprising hypromellose, titanium dioxide, triacetin, and iron
oxide yellow; and wherein:
[0064] the median overall survival of the patients is extended as
compared to the median overall survival of patients taking
everolimus; and wherein
[0065] one or both of progression-free survival (PFS) and objective
response rate are also extended as compared to patients taking
everolimus.
[0066] In another aspect, the invention is directed to a method of
treating renal cell carcinoma in human patients in need of such
treatment who have received prior everolimus therapy, comprising
administering to the patients 60 mg of cabozantinib (S)-malate free
base equivalent (FBE) sufficient to achieve one, two, three, four,
five, six, seven, or eight effects selected from the group
consisting of:
[0067] a median time to peak plasma concentration (Tmax) from 2 to
5 hours post-dose;
[0068] a Cmax of 200 to 500 ng/mL;
[0069] an AUC.sub.0-24 of 2500 to 5200 ng*h/mL;
[0070] an AUC.sub.0-t of 18,000 to 42,000 ng*h/mL;
[0071] an AUC.sub.0-.infin. of 19,000 to 45,000 ng*h/mL;
[0072] an oral volume distribution (Vz/F) of 100 to 600 L;
[0073] a terminal half-life of 90 to 135 h; and
[0074] a clearance at steady state (CL/F) of 0.7 to 3.9 L/h;
wherein:
the cabozantinib (S)-malate is administered as a tablet formulation
comprising approximately (% w/w):
[0075] 31-32 percent by weight of cabozantinib, (S)-malate
salt;
[0076] 39-40 percent by weight of microcrystalline cellulose;
[0077] 19-20 percent by weight of lactose;
[0078] 2.5-3.5 percent by weight of hydroxypropyl cellulose;
[0079] 5.5-6.5 percent by weight of croscarmellose sodium;
[0080] 0.25-0.35 percent by weight of colloidal silicon
dioxide;
[0081] 0.7-0.8 percent by weight of magnesium stearate; and further
comprising:
[0082] 3.9-4.1 percent by weight of a film coating material
comprising hypromellose, titanium dioxide, triacetin, and iron
oxide yellow; and wherein:
[0083] the median overall survival of the patients is extended as
compared to the median overall survival of patients taking
everolimus; and wherein
[0084] one or both of progression-free survival (PFS) and objective
response rate are also extended as compared to patients taking
everolimus.
[0085] In another aspect the invention is directed to a method of
treating advanced renal cell carcinoma in patients in need of such
treatment who have received prior antiangiogenic therapy selected
from the group consisting of sunitinib therapy, pazopanib therapy,
and anti-PD-1/PD-L1 immune checkpoint inhibitor therapy, comprising
administering cabozantinib
##STR00003##
or a pharmaceutically acceptable salt thereof, wherein
progression-free survival (PFS), and one or both of overall
survival (OS) and objective response rate (ORR) are extended over
patients who have received everolimus or another anti-angiogenic
therapy. In this and other aspects, cabozantinib is administered as
cabozantinib (S)-malate.
[0086] In a further aspect, the invention is directed to a method
of optimizing the treatment of a renal carcinoma patient with a
tyrosine kinase inhibitor (TKI) comprising the step of: quantifying
the patient's response to one or more dosing regimens of said TKI
inhibitor with a model employing Equation 1:
dY dt = k grow Y - ( k dmax + k dmax tol e - k tol t ) Cavg ( EC 50
+ Cavg ) Y Equation .times. .times. 1 ##EQU00001## [0087] where:
[0088] dY/dt is the change in tumor diameter per unit time [0089]
k.sub.grow is the first-order growth rate constant [0090]
k.sub.dmax is the maximum non-attenuating drug induced tumor decay
rate [0091] k.sub.dmax_tol is the maximum loss in the decay rate
due to resistance [0092] k.sub.tol is the rate constant which
governs the rate of attenuation [0093] EC.sub.50 is the
cabozantinib concentration yielding one-half of the current tumor
decay rate [0094] Cavg is the individual predicted daily average
cabozantinib concentration.
[0095] In this and other aspects, the TKI is cabozantinib as the
S-malate salt.
[0096] A further aspect of the present invention is to provide the
use of cabozantinib as the S-malate salt for treating advanced
renal cell carcinoma in a human patient as described herein. A
further aspect of the present invention is to provide the use of
cabozantinib as the S-malate salt in the manufacture of a
medicament for treating advanced renal cell carcinoma in a human
patient as described herein.
[0097] Additional embodiments and advantages of the invention will
be set forth in part in the description that follows, and will flow
from the description, or can be learned by practice of the
invention. The embodiments and advantages of the invention will be
realized and attained by means of the elements and combinations
particularly pointed out in the appended claims.
[0098] It is to be understood that both the foregoing summary and
the following detailed description are exemplary and explanatory
only and are not restrictive of the invention as claimed.
BRIEF DESCRIPTION OF THE DRAWINGS
[0099] FIG. 1.1 depicts the progression-free survival rates in
Study 1 (First 375 Randomized).
[0100] FIG. 1.2 depicts the overall survival in Study 1 (Intent to
Treat, ITT).
[0101] FIG. 1.3 depicts a flow chart of patient disposition through
Dec. 31, 2015.
[0102] FIG. 1.4 is a Kaplan-Meier plot of overall survival through
Dec. 31, 2015. All 658 randomized patients were included in the
analysis.
[0103] FIG. 1.5A and FIG. 1.51B depict Forest plots of overall
survival and progression-free survival.
[0104] FIG. 1.6A and FIG. 1.6B depict Kaplan-Meier Plots of Overall
Survival for Subgroups of Tumor MET Expression.
[0105] FIG. 1.7 is a Kaplan-Meier plot of progression-free survival
as of May 22, 2015.
[0106] FIG. 1.8 depicts a schematic view of the METEOR study
design.
[0107] FIG. 1.9 depicts the statistical design of the METEOR
study.
[0108] FIG. 1.10 depicts the patient disposition for the METEOR
study.
[0109] FIG. 1.11 depicts the overall survival of patients by the
MSKCC risk group: favorable risk, intermediate risk, and poor
risk.
[0110] FIG. 1.12 depicts the overall survival of patients by prior
VEGFR TKI treatment: sunitinib as only prior VEGFR TKI and
pazopanib as only prior VEGFR TKI.
[0111] FIG. 1.13 depicts the overall survival of patients by
presence of bone metastases: bone metastases and bone and visceral
metastases.
[0112] FIG. 1.14 depicts patient disposition (ITT Population).
[0113] FIG. 1.15A and FIG. 1.15B plot absolute FKSI scores over
time (ITT Population).
[0114] FIG. 1.16 depicts the effect of baseline FKSI-DRS on OS (ITT
Population). CI, confidence interval; DRS, disease-related
symptoms; FKSI, FACT Kidney Symptom Index; HR, hazard ratio; mo,
month; OS, overall survival; QoL, quality of life.
[0115] FIG. 2.1 depicts the quality of life instruments and quality
of life assessment schedule.
[0116] FIG. 2.2A and FIG. 2.2B depict FKSI-19 total scores over
time.
[0117] FIG. 2.3 depicts the time to deterioration (TTD) in the
overall population.
[0118] FIG. 2.4A and FIG. 2.4B depict the effect of baseline bone
metastases on TTD.
[0119] FIG. 3.1 depicts progression free survival based on
metastatic site and tumor burden.
[0120] FIG. 3.2 depicts overall survival based on metastatic site
and tumor burden.
[0121] FIG. 3.3 depicts the Kaplan-Meier analysis of overall
survival.
[0122] FIG. 4.1 depicts the METEOR trial within a trial statistical
design.
[0123] FIG. 4.2A and FIG. 4.2B depict sample plots from statistical
studies. Example 1 depicts the potential inability to estimate
medians. Example 2 depicts the potential to mask non-proportional
hazards.
[0124] FIG. 4.3 depicts the Kaplan-Meier analysis of progression
free survival.
[0125] FIG. 4.4 depicts the evaluation of proportional hazards
assumption for progression free survival by log-log plots.
[0126] FIG. 5.1 depicts the METEOR enrollment in countries as a
percentage of total enrolled patients.
[0127] FIG. 5.2 provides Forest plots of progression free survival
per IRC by Region.
[0128] FIG. 5.3 provides Forest plots of overall survival per IRC
by Region.
[0129] FIG. 8.1 depicts the progression-free survival per
independent radiology committee (IRC) in all 658 randomized
patients.
[0130] FIG. 8.2 depicts the overall survival over 30 months.
[0131] FIG. 8.3. depicts the study design.
[0132] FIG. 8.4 shows Kaplan-Meier analyses of progression-free
survival in patients with bone metastases, patients with bone and
visceral metastases, and patients without bone metastases.
[0133] FIG. 8.5 shows Kaplan-Meier analyses of overall survival in
patients with bone metastases, patients with bone and visceral
metastases, and patients without bone metastases.
[0134] FIG. 8.6 depicts the effect of cabozantinib on bone markers
for patients with bone metastases at baseline.
[0135] FIG. 8.7 depicts the effect of cabozantinib on bone markers
for patients without bone metastases at baseline.
[0136] FIG. 9.1 depicts the progression free survival of subgroups
based on prior therapy (sunitinib, pazopanib, or
Anti-PD-1/PD-L1).
[0137] FIG. 9.2 depicts the Forest Plot analysis of overall
survival.
[0138] FIG. 9.3 depicts the overall survival of subgroups based on
prior therapy (sunitinib, pazopanib, or Anti-PD-1/PD-L1).
[0139] FIG. 9.4 depicts the analysis of progression free
survival.
[0140] FIG. 9.5 depicts the progression free survival and response
in Anti-PD-1/PD-L1 subgroup.
[0141] FIG. 10.1 depicts the Cabozantinib PopPK Model.
[0142] FIG. 10.2A, FIG. 10.2B, FIG. 10.2C, and FIG. 10.2D depict
the PopPK Goodness of Fit by Study and Dose.
[0143] FIG. 10.3 depicts the Impact of Covariates Gender and Asian
Race on Steady State Cabozantinib Exposure.
[0144] FIG. 10.4 depicts the Predicted Progression-Free Survival
Curves for Selected Average Cabozantinib Concentrations.
[0145] FIG. 10.5 depicts the Predicted Median Percent Change from
Baseline Tumor Diameter for Selected Simulated Starting Doses of
Cabozantinib.
DETAILED DESCRIPTION
[0146] In preferred embodiments, CABOMETYX.RTM. is indicated for
the treatment of patients with advanced renal cell carcinoma (RCC)
who have received prior anti-angiogenic therapy. Prior
anti-angiogenic therapy includes, for instance, a therapy selected
from the group consisting of axitinib, pazopanib, sorafenib,
sunitinib, everolimus, temsirolimus, bevacizumab, interleukins,
interferon-.alpha., peginterferon, nivolumab, AMP-514, and
atezolizumab. Dosing information for prior anti-angiogenic therapy
is publically available. For example: [0147] axitinib (Inlyta.RTM.)
is used to treat patients with advanced renal cell carcinoma after
failure of one prior systemic therapy. It is administered at a
starting dose of 5 mg orally once daily, approximately 12 hours
apart, with or without food. See
www.accessdata.fda.gov/drugsatfda_docs/label/2012/2023241bl.pdf
(last visited Apr. 14, 2017); [0148] pazopanib (Votrient.RTM.) is
used to treat patients with advanced renal cell carcimona and
advanced soft tissue sarcoma who have received prior therapy. It is
administered at a dose of 800 mg orally once daily without food.
See
www.accessdata.fda.gov/drugsatfda_docs/label/2015/022465s020lbledt.pdf
(last visited Apr. 14, 2017); [0149] sorafenib (Nexavar.RTM.) is
used to treat patients with unrecectable metastatic carcinoma and
advanced renal cell carcinoma. It is administered at a dose of 400
mg (2 tablets) orally twice daily without food. See
www.accessdata.fda.gov/drugsatfda_docs/labe/2010/021923s008s009lbl.pdf
(last visited Apr. 14, 2017); [0150] sunitinib (Sutent.RTM.) is
used to treat patients with gastrointestinal stromal tumor,
advanced renal cell carcinoma, and progressive, well-differentiated
pancreatic neuroendocrine tumors in patients with unrectable
locally advanced or metastatic disease. It is administered at a
dose of 50 mg orally once daily with or without food, four weeks on
treatment, followed by two weeks off. See
www.accessdata.fda.gov/drugsatfda_docs/label/2011/021938s13s17s181bl.pdf
(last visited Apr. 14, 2017); [0151] everolimus (Afinitor.RTM.) is
used to treat patients with advanced renal cell carcinoma and
subependymal giant cell astrocytoma (SEGA) associated with tuberous
sclerosis (TS) who require therapeutic intervention but are not
candidates for curative surgical resection. It is administered
orally at a dose of 10 mg once daily with or without food. See
www.accessdata.fda.gov/drugsatfda_docs/label/2010/022334s6lbl.pdf
(last visited Apr. 14, 2017); [0152] temsirolimus (Torisel.RTM.)
(25 mg) is used to treat patients with advanced renal cell
carcinoma. It is infused over a 30 to 60 minute period once a week.
Treatment is continued until progression or unacceptable toxicity.
See
www.accessdata.fda.gov/drugsatfda_docs/label/2011/022088s002s004s005s007s-
010s 0121bl.pdf (last visited Apr. 14, 2017); [0153] bevacizumab
(Avastin.RTM.) is used to treat patients with metastatic colorectal
cancer, with intravenous 5-fluorouracil-based chemotherapy for
first- or second-line treatment; metastatic colorectal cancer, with
fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based
chemotherapy for second-line treatment in patients who have
progressed on a first-line Avastin containing regimen; non-squamous
non-small cell lung cancer, with carboplatin and paclitaxel for
first line treatment of unresectable, locally advanced, recurrent
or metastatic disease; glioblastoma, as a single agent for adult
patients with progressive disease following prior therapy; and
cervical cancer, in combination with paclitaxel and cisplatin or
paclitaxel and topotecan in persistent, recurrent, or metastatic
disease. It is administered at the recommended dose of 10 mg/kg
every 2 weeks in combination with interferon alfa for the treatment
of metastatic renal cell carcinoma). Bevacizumab is available in
100 mg/4 mL or 400 mg/16 mL single use vials. See
www.accessdata.fda.gov/drugsatfda_docs/label/2014/125085s301
lbl.pdf (last visited Apr. 14, 2017); [0154] nivolumab
(Opdivo.RTM.) is used to treat patients with BRAF V600 wild-type
unresectable or metastatic melanoma, as a single agent; BRAF V600
mutation-positive unresectable or metastatic melanoma, as a single
agent. This indication is approved under accelerated approval based
on progression-free survival. Continued approval for this
indication may be contingent upon verification and description of
clinical benefit in the confirmatory trials; unresectable or
metastatic melanoma, in combination with ipilimumab. This
indication is approved under accelerated approval based on
progression-free survival. Continued approval for this indication
may be contingent upon verification and description of clinical
benefit in the confirmatory trials, metastatic non-small cell lung
cancer and progression on or after platinum-based chemotherapy.
Patients with EGFR or ALK genomic tumor aberrations should have
disease progression on FDA-approved therapy for these aberrations
prior to receiving OPDIVO; Advanced renal cell carcinoma who have
received prior anti-angiogenic therapy; Classical Hodgkin lymphoma
that has relapsed or progressed after autologous hematopoietic stem
cell transplantation (HSCT) and post-transplantation brentuximab
vedotin. This indication is approved under accelerated approval
based on overall response rate. Continued approval for this
indication may be contingent upon verification and description of
clinical benefit in confirmatory trials. It is administered as
follows: (i) unresectable or metastatic melanoma--OPDIVO 3 mg/kg
every 2 weeks; OPDIVO with ipilimumab: OPDIVO 1 mg/kg, followed by
ipilimumab; on the same day, every 3 weeks for 4 doses, then OPDIVO
3 mg/kg every 2 weeks; (ii) metastatic non-small cell lung
cancer--OPDIVO 3 mg/kg every 2 weeks; (iii) advanced renal cell
carcinoma--OPDIVO 3 mg/kg every 2 weeks; (iv) classical Hodgkin
lymphoma--OPDIVO 3 mg/kg every 2 weeks. See
www.accessdata.fda.gov/drugsatfda_docs/label/2014/125554lbl.pdf
(last visted Apr. 14, 2017); and [0155] Atezolizumab
(Tecentriq.RTM.) is used to treat patients with (i) locally
advanced or metastatic urothelial carcinoma who have disease
progression during or following platinum-containing chemotherapy;
or have disease progression within 12 months of neoadjuvant or
adjuvant treatment with platinum-containing chemotherapy. This
indication is approved under accelerated approval based on tumor
response rate and duration of response. Continued approval for this
indication may be contingent upon verification and description of
clinical benefit in confirmatory trials; (ii) metastatic non-small
cell lung cancer who have disease progression during or following
platinum-containing chemotherapy. Patients with EGFR or ALK genomic
tumor aberrations should have disease progression on FDA-approved
therapy for these aberrations prior to receiving TECENTRIQ. It is
administered as an intravenous infusion (1200 mg) over 60 minutes
every 3 weeks. It is diluted prior to intravenous infusion. See
www.accessdata.fda.gov/drugsatfda_docs/label/2016/7610411bl.pdf
(last visted Apr. 14, 2017).
[0156] In preferred embodiments, CABOMETYX.RTM. tablets should not
be substituted with cabozantinib capsules. The recommended daily
dose of CABOMETYX.RTM. is 60 mg. CABOMETYX.RTM. should not be
administered with food. Patients should not to eat for at least 2
hours before and at least 1 hour after taking CAIBOMETYX.RTM..
Treatment should be continued until the patient no longer
experiences clinical benefit or experiences unacceptable toxicity.
CABOMETYX.RTM. tablet should be swallowed whole. CABOMETYX.RTM.
tablet should not be crushed. A missed dose should not be taken
within 12 hours of the next dose. Foods (e.g., grapefruit,
grapefruit juice) or nutritional supplements that are known to
inhibit cytochrome P450 should not be ingested during
CABOMETYX.RTM. treatment.
[0157] In preferred embodiments, treatment with CABOMETYX.RTM.
should be stopped at least 28 days prior to scheduled surgery,
including dental surgery. CABOMETYX.RTM. should be withheld for NCI
CTCAE Grade 4 adverse reactions, and for Grade 3 or intolerable
Grade 2 adverse reactions that cannot be managed with a dose
reduction or supportive care. Upon resolution/improvement (i.e.,
return to baseline or resolution to Grade 1) of an adverse
reaction, the dose should be reduced as follows: [0158] If
previously receiving 60 mg daily dose, resume treatment at 40 mg
daily. [0159] If previously receiving 40 mg daily dose, resume
treatment at 20 mg daily. [0160] If previously receiving 20 mg
daily dose, resume at 20 mg if tolerated, otherwise, discontinue
CABOMETYX.RTM..
[0161] In preferred embodiments, CABOMETYX.RTM. should be
permanently discontinued for any of the following: [0162]
development of unmanageable fistula or GI perforation; [0163]
severe hemorrhage; [0164] arterial thromboembolic event (e.g.,
myocardial infarction, cerebral infarction); [0165] hypertensive
crisis or severe hypertension despite optimal medical management;
[0166] nephrotic syndrome; [0167] reversible posterior
leukoencephalopathy syndrome.
[0168] In preferred embodiments, in patients concurrently taking a
strong CYP3A4 inhibitor, the daily CABOMETYX.RTM. dose should be
reduced by 20 mg (for example, from 60 mg to 40 mg daily or from 40
mg to 20 mg daily). The dose that was used prior to initiating the
CYP3A4 inhibitor should be resumed 2 to 3 days after
discontinuation of the strong inhibitor.
[0169] In preferred embodiments, in patients concurrently taking a
strong CYP3A4 inducer, the daily CABOMETYX.RTM. dose should be
increased by 20 mg (for example, from 60 mg to 80 mg daily or from
40 mg to 60 mg daily) as tolerated. The dose that was used prior to
initiating the CYP3A4 inducer should be resumed 2 to 3 days after
discontinuation of the strong inducer. The daily dose of
CABOMETYX.RTM. should not exceed 80 mg.
[0170] In preferred embodiments, in patients with mild or moderate
hepatic impairment, the starting dose of CABOMETYX.RTM. should be
reduced to 40 mg once daily. CABOMETYX.RTM. is not recommended for
use in patients with severe hepatic impairment.
[0171] There are no contraindications for CABOMETYX.RTM..
Cabozantinib Tablet Formulations
[0172] As indicated previously, the invention relates in part to a
method of treating advanced renal cell carcinoma (RCC) in human
patients who have received prior anti-angiogenic therapy, wherein
progression-free survival (PFS), and one or both of overall
survival (OS) and objective response rate (ORR) are extended as
compared to patients who have received prior anti-angiogenic
therapy.
[0173] The invention also relates to a method of treating advanced
renal cell carcinoma in a human patient who has received prior
anti-angiogenic therapy comprising administering to the patient an
amount of cabozantinib (S)-malate sufficient to achieve one or more
effects selected from the group consisting of a median time to peak
plasma concentration (Tmax) of from approximately 3.2 to 3.8 hours
post-dose; and a Cmax of 310 to 350 ng/mL, wherein progression-free
survival (PFS), and one or both of overall survival (OS) and
objective response rate (ORR) are extended as compared to patients
who have received prior anti-angiogenic therapy.
[0174] The invention also relates to a method of treating advanced
renal cell carcinoma in human patients in need of such treatment
who has received prior everolimus therapy, comprising administering
to the patients an amount of cabozantinib (S)-malate free base
equivalent (FBE) sufficient to achieve one, two, three, four, or
five effects selected from the group consisting of:
[0175] a Cmax of 30 to 500 ng/mL;
[0176] an AUC.sub.0-24 of 500 to 5200 ng*h/mL;
[0177] an AUC.sub.0-t of 4500 to 42,000 ng*h/mL;
[0178] an AUC.sub.0-.infin. of 5000 to 45,000 ng*h/mL;
[0179] a terminal half-life of 90 to 165 h;
[0180] wherein the cabozantinib (S)-malate is administered as a
tablet formulation comprising approximately (% w/w):
[0181] 31-32 percent by weight of cabozantinib, (S)-malate
salt;
[0182] 39-40 percent by weight of microcrystalline cellulose;
[0183] 19-20 percent by weight of lactose;
[0184] 2.5-3.5 percent by weight of hydroxypropyl cellulose;
[0185] 5.5-6.5 percent by weight of croscarmellose sodium;
[0186] 0.25-0.35 percent by weight of colloidal silicon
dioxide;
[0187] 0.7-0.8 percent by weight of magnesium stearate; and further
comprising:
[0188] 3.9-4.1 percent by weight of a film coating material
comprising hypromellose, titanium dioxide, triacetin, and iron
oxide yellow; and wherein:
[0189] the median overall survival of the patients is extended as
compared to the median overall survival of patients taking
everolimus; and wherein
[0190] one or both of progression-free survival (PFS) and objective
response rate are also extended as compared to patients taking
everolimus.
[0191] The invention also relates to a method of treating advanced
renal cell carcinoma in human patients in need of such treatment
who has received prior everolimus therapy, comprising administering
to the patients 20 mg, 40 mg, or 60 mg of cabozantinib (S)-malate
free base equivalent (FBE) sufficient to achieve one, two, three,
four, or five effects selected from the group consisting of:
[0192] a Cmax of 30 to 500 ng/mL;
[0193] an AUC.sub.0-24 of 500 to 5200 ng*h/mL;
[0194] an AUC.sub.0-t of 4500 to 42,000 ng*h/mL;
[0195] an AUC.sub.0-.infin. of 5000 to 45,000 ng*h/mL;
[0196] a terminal half-life of 90 to 165 h;
[0197] wherein the cabozantinib (S)-malate is administered as a
tablet formulation comprising approximately (% w/w):
[0198] 31-32 percent by weight of cabozantinib, (S)-malate
salt;
[0199] 39-40 percent by weight of microcrystalline cellulose;
[0200] 19-20 percent by weight of lactose;
[0201] 2.5-3.5 percent by weight of hydroxypropyl cellulose;
[0202] 5.5-6.5 percent by weight of croscarmellose sodium;
[0203] 0.25-0.35 percent by weight of colloidal silicon
dioxide;
[0204] 0.7-0.8 percent by weight of magnesium stearate; and further
comprising:
[0205] 3.9-4.1 percent by weight of a film coating material
comprising hypromellose, titanium dioxide, triacetin, and iron
oxide yellow; and wherein:
[0206] the median overall survival of the patients is extended as
compared to the median overall survival of patients taking
everolimus; and wherein
[0207] one or both of progression-free survival (PFS) and objective
response rate are also extended as compared to patients taking
everolimus.
[0208] The invention also relates to a method of treating advanced
renal cell carcinoma in a human patient who has received prior
anti-angiogenic therapy comprising administering to the patient an
amount of cabozantinib (S)-malate FBE sufficient to achieve one,
two, three, four, five, six, seven, or eight effects selected from
the group consisting of:
[0209] a median time to peak plasma concentration (Tmax) from 2 to
5 hours post-dose;
[0210] a Cmax of 200 to 500 ng/mL;
[0211] an AUC.sub.0-24 of 2500 to 5200 ng*h/mL;
[0212] an AUC.sub.0-t of 18,000 to 42,000 ng*h/mL;
[0213] an AUC.sub.0-.infin. of 19,000 to 45,000 ng*h/mL;
[0214] an oral volume distribution (Vz/F) of 100 to 600 L;
[0215] a terminal half-life of 90 to 135 h; and
[0216] a clearance at steady state (CL/F) of 0.7 to 3.9 L/h;
[0217] wherein the cabozantinib (S)-malate is administered as a
tablet formulation comprising approximately (% w/w):
[0218] 31-32 percent by weight of cabozantinib, (S)-malate
salt;
[0219] 39-40 percent by weight of microcrystalline cellulose;
[0220] 19-20 percent by weight of lactose;
[0221] 2.5-3.5 percent by weight of hydroxypropyl cellulose;
[0222] 5.5-6.5 percent by weight of croscarmellose sodium;
[0223] 0.25-0.35 percent by weight of colloidal silicon
dioxide;
[0224] 3.9-4.1 percent by weight of magnesium stearate; and further
comprising:
[0225] 3.9-4.1 percent by weight of a film coating material
comprising hypromellose, titanium dioxide, triacetin, and iron
oxide yellow;
[0226] wherein progression-free survival (PFS), and one or both of
overall survival (OS) and objective response rate (ORR) are
extended as compared to patients who have received prior
anti-angiogenic therapy.
[0227] The invention also relates to a method of treating advanced
renal cell carcinoma in a human patient who has received prior
anti-angiogenic therapy comprising administering to the patient 60
mg of cabozantinib (S)-malate FBE sufficient to achieve one, two,
three, four, five, six, seven, or eight effects selected from the
group consisting of: a median time to peak plasma concentration
(Tmax) from 2 to 5 hours post-dose;
[0228] a Cmax of 200 to 500 ng/mL;
[0229] an AUC.sub.0-24 of 2500 to 5200 ng*h/mL;
[0230] an AUC.sub.0-t of 18,000 to 42,000 ng*h/mL;
[0231] an AUC.sub.0-.infin. of 19,000 to 45,000 ng*h/mL;
[0232] an oral volume distribution (Vz/F) of 100 to 600 L;
[0233] a terminal half-life of 90 to 135 h; and
[0234] a clearance at steady state (CL/F) of 0.7 to 3.9 L/h;
wherein the cabozantinib (S)-malate is administered as a tablet
formulation comprising approximately (% w/w):
[0235] 31-32 percent by weight of cabozantinib, (S)-malate
salt;
[0236] 39-40 percent by weight of microcrystalline cellulose;
[0237] 19-20 percent by weight of lactose;
[0238] 2.5-3.5 percent by weight of hydroxypropyl cellulose;
[0239] 5.5-6.5 percent by weight of croscarmellose sodium;
[0240] 0.25-0.35 percent by weight of colloidal silicon
dioxide;
[0241] 0.7-0.8 percent by weight of magnesium stearate; and further
comprising:
[0242] 3.9-4.1 percent by weight of a film coating material
comprising hypromellose, titanium dioxide, triacetin, and iron
oxide yellow;
[0243] wherein progression-free survival (PFS), and one or both of
overall survival (OS) and objective response rate (ORR) are
extended as compared to patients who have received prior
anti-angiogenic therapy.
[0244] Cabozantinib is administered as a tablet comprising
cabozantinib (S)-malate, microcrystalline cellulose, anhydrous
lactose, hydroxypropyl cellulose, croscarmellose sodium, colloidal
silicon dioxide magnesium stearate, and film coating comprising
hypromellose, titanium dioxide, triacetin, and iron oxide
yellow.
[0245] In particular, CABOMETYX.RTM. is administered as a tablet
comprising cabozantinib (S)-malate, microcrystalline cellulose,
anhydrous lactose, hydroxypropyl cellulose, croscarmellose sodium,
colloidal silicon dioxide magnesium stearate, and film coating
comprising hypromellose, titanium dioxide, triacetin, and iron
oxide yellow.
[0246] In an embodiment, the cabozantinib (S)-malate is
administered as a tablet formulation comprising approximately:
[0247] 30-32 percent by weight of cabozantinib, (S)-malate
salt;
[0248] 38-40 percent by weight of microcrystalline cellulose;
[0249] 18-22 percent by weight of lactose;
[0250] 2-4 percent by weight of hydroxypropyl cellulose;
[0251] 4-8 percent by weight of croscarmellose sodium;
[0252] 0.2-0.6 percent by weight of colloidal silicon dioxide;
[0253] 0.5-1 percent by weight of magnesium stearate; and further
comprising:
[0254] a film coating material comprising hypromellose, titanium
dioxide, triacetin, and iron oxide yellow.
[0255] In another embodiment, the cabozantinib (S)-malate is
administered as a tablet formulation comprises approximately:
[0256] 31-32 percent by weight of cabozantinib, (S)-malate
salt;
[0257] 39-40 percent by weight of microcrystalline cellulose;
[0258] 19-20 percent by weight of lactose;
[0259] 2.5-3.5 percent by weight of hydroxypropyl cellulose;
[0260] 5.5-6.5 percent by weight of croscarmellose sodium;
[0261] 0.25-0.35 percent by weight of colloidal silicon
dioxide;
[0262] 0.7-0.8 percent by weight of magnesium stearate; and further
comprising:
[0263] 3.9-4.1 percent by weight of a film coating material
comprising hypromellose, titanium dioxide, triacetin, and iron
oxide yellow.
[0264] In another embodiment the cabozantinib (S)-malate is
administered as a tablet formulation selected from the group
consisting of:
TABLE-US-00001 Theoretical Quantity (mg/unit dose) Ingredient 20-mg
Tablet* 40-mg Tablet* 60-mg Tablet* Cabozantinib (S)-malate 25.34
50.69 76.03 Microcrystalline 31.08 62.16 93.24 Cellulose, PH-102
Lactose Anhydrous, 60M 15.54 31.07 46.61 Hydroxypropyl Cellulose,
2.400 4.800 7.200 EXF Croscarmellose Sodium 4.800 9.600 14.40
Colloidal Silicon Dioxide 0.2400 0.4800 0.7200 Magnesium Stearate
0.6000 1.200 1.800 (Non-Bovine) Opadry.sup. .RTM. Yellow 3.200
6.400 9.600 (03K92254) Total Tablet weight 83.20 166.4 249.6 *Free
Base Equivalent
[0265] In another embodiment, the cabozantinib (S)-malate is
administered as a tablet formulation containing 20, 40, or 60 mg of
cabozantinib. 60 mg tablets are yellow film-coated, oval shaped
with no score, debossed with "XL" on one side and "60" on the other
side of the tablet available in bottles of 30 tablet: NDC
42388-023-26. 40 mg tablets are yellow film-coated, triangle shaped
with no score, debossed with "XL" on one side and "40" on the other
side of the tablet; available in bottles of 30 tablets: NDC
42388-025-26. 20 mg tablets are yellow film-coated, round shaped
with no score, debossed with "XL" on one side and "20" on the other
side of the tablet; available in bottles of 30 tablets: NDC
42388-024-26.
[0266] In another embodiment, CABOMETYX.RTM. should be stored at
20.degree. C. to 25.degree. C. (68.degree. F. to 77.degree. F.);
excursions are permitted from 15.degree. C. to 30.degree. C.
(59.degree. F. to 86.degree. F.) [see USP Controlled Room
Temperature].
[0267] In a further embodiment, the cabozantinib (S)-malate is
administered once daily.
[0268] In a further embodiment, the 60 mg of cabozantinib is
administered once daily as the CABOMETYX.RTM. tablet formulation as
described herein.
[0269] In a further aspect, the invention described herein relates
to a method of treating renal cell carcinoma in a human patient who
has received prior anti-angiogenic therapy, comprising
administering to the patient 60 mg cabozantinib (S)-malate (free
base equivalent) sufficient to achieve one, two, three, four, five,
six, seven, or eight effects selected from the group consisting of:
[0270] a median time to peak plasma concentration (Tmax) from 2 to
5 hours post-dose;
[0271] a Cmax of 200 to 500 ng/mL;
[0272] an AUC.sub.0-24 of 2500 to 5200 ng*h/mL;
[0273] an AUC.sub.0-t of 18,000 to 42,000 ng*h/mL;
[0274] an AUC.sub.0-.infin. of 19,000 to 45,000 ng*h/mL;
[0275] an oral volume distribution (Vz/F) of 100 to 600 L;
[0276] a terminal half-life of 90 to 135 h; and
[0277] a clearance at steady state (CL/F) of 0.7 to 3.9 L/h;
[0278] wherein the cabozantinib (S)-malate is administered as a
tablet formulation comprising approximately (% w/w): 31-32 percent
by weight of cabozantinib, (S)-malate salt;
[0279] 39-40 percent by weight of microcrystalline cellulose;
[0280] 19-20 percent by weight of lactose;
[0281] 2.5-3.5 percent by weight of hydroxypropyl cellulose;
[0282] 5.5-6.5 percent by weight of croscarmellose sodium;
[0283] 0.25-0.35 percent by weight of colloidal silicon
dioxide;
[0284] 0.7-0.8 percent by weight of magnesium stearate; and further
comprising:
[0285] 3.9-4.1 percent by weight of a film coating material
comprising hypromellose, titanium dioxide, triacetin, and iron
oxide yellow;
[0286] wherein progression-free survival (PFS), and one or both of
overall survival (OS) and objective response rate (ORR) are
extended as compared to patients who have received prior
anti-angiogenic therapy.
[0287] In another embodiment, the cabozantinib (S)-malate is
administered as a tablet formulation containing 20, 40, or 60 mg of
cabozantinib.
[0288] In a further embodiment, the cabozantinib (S)-malate is
administered in an amount sufficient to achieve one, two, three,
four, five, six, seven, or eight effects selected from the group
consisting of:
[0289] a median time to peak plasma concentration (Tmax) from 2 to
5 hours post-dose;
[0290] a Cmax of 200 to 500 ng/mL;
[0291] an AUC.sub.0-24 of 2500 to 5200 ng*h/mL;
[0292] an AUC.sub.0-t of 18,000 to 42,000 ng*h/mL;
[0293] an AUC.sub.0-.infin. of 19,000 to 45,000 ng*h/mL;
[0294] an oral volume distribution (Vz/F) of 100 to 600 L;
[0295] a terminal half-life of 90 to 135 h; and
[0296] a clearance at steady state (CL/F) of 0.7 to 3.9 L/h
[0297] In a further embodiment, the cabozantinib (S)-malate is
administered in an amount sufficient to achieve one, two, three,
four, five, six, seven, or eight effects selected from the group
consisting of:
[0298] a median time to peak plasma concentration (Tmax) from 2.5
to 4.5 hours post-dose;
[0299] a Cmax of 250 to 450 ng/mL;
[0300] an AUC.sub.0-24 of 3000 to 4700 ng*h/mL;
[0301] an AUC.sub.0-t of 23,000 to 37,000 ng*h/mL;
[0302] an AUC.sub.0-.infin. of 24,000 to 40,000 ng*h/mL;
[0303] an oral volume distribution (Vz/F) of 150 to 550 L;
[0304] a terminal half-life of 100 to 125 h; and
[0305] a clearance at steady state (CL/F) of 1.2 to 3.2 L/h.
[0306] In a further embodiment, the cabozantinib (S)-malate is
administered in an amount sufficient to achieve one, two, three,
four, five, six, seven, or eight effects selected from the group
consisting of:
[0307] a median time to peak plasma concentration (Tmax) from 3 to
4 hours post-dose;
[0308] a Cmax of 300 to 400 ng/mL;
[0309] an AUC.sub.0-24 of 3500 to 4200 ng*h/mL;
[0310] an AUC.sub.0-t of 28,000 to 32,000 ng*h/mL;
[0311] an AUC.sub.0-.infin. of 29,000 to 35,000 ng*h/mL;
[0312] an oral volume distribution (Vz/F) of 200 to 500 L;
[0313] a terminal half-life of 110 to 115 h; and
[0314] a clearance at steady state (CL/F) of 1.2 to 3.2
[0315] In a further embodiment, the cabozantinib (S)-malate is
administered in an amount sufficient to achieve one, two, three,
four, five, six, seven, or eight effects selected from the group
consisting of:
[0316] a median time to peak plasma concentration (Tmax) from 3.2
to 3.8 hours post-dose; a Cmax of 310 to 350 ng/mL;
[0317] an AUC.sub.0-24 of 3700 to 4000 ng*h/mL;
[0318] an AUC.sub.0-t of 29,000 to 30,000 ng*h/mL;
[0319] an AUC.sub.0-.infin. of 30,000 to 33,000 ng*h/mL;
[0320] an oral volume distribution (Vz/F) of 300 to 400 L;
[0321] a terminal half-life of 110 to 114 h; and
[0322] a clearance at steady state (CL/F) of 2 to 3.
Warnings and Precautions
[0323] Severe hemorrhage occurred with CABOMETYX.RTM.. The
incidence of Grade .gtoreq.3 hemorrhagic events was 2.1% in
CABOMETYX-treated patients and 1.6% in everolimus-treated patients.
Fatal hemorrhages also occurred in the cabozantinib clinical
program. CABOMETYX.RTM. should not be administered to patients that
have or are at risk for severe hemorrhage.
[0324] In a randomized study in renal cell carcinoma, fistulas were
reported in 1.2% (including 0.6% anal fistula) of CABOMETYX-treated
patients and 0% of everolimus-treated patients. Gastrointestinal
(GI) perforations were reported in 0.9% of CABOMETYX-treated
patients and 0.6% of everolimus-treated patients. Fatal
perforations occurred in the cabozantinib clinical program.
Patients should be monitored for symptoms of fistulas and
perforations. CABOMETYX.RTM. should be discontinued in patients who
experience a fistula which cannot be appropriately managed or a GI
perforation.
[0325] CABOMETYX.RTM. treatment results in an increased incidence
of thrombotic events. Venous thromboembolism was reported in 7.3%
of CABOMETYX-treated patients and 2.5% of everolimus-treated
patients. Pulmonary embolism occurred in 3.9% of CABOMETYX-treated
patients and 0.3% of everolimus-treated patients. Events of
arterial thromboembolism were reported in 0.9% of CABOMETYX-treated
patients and 0.3% of everolimus-treated patients. Fatal thrombotic
events occurred in the cabozantinib clinical program.
CABOMETYX.RTM. should be discontinued in patients who develop an
acute myocardial infarction or any other arterial thromboembolic
complication.
[0326] CABOMETYX.RTM. treatment results in an increased incidence
of treatment-emergent hypertension. Hypertension was reported in
37% (15% Grade .gtoreq.3) of CABOMETYX-treated patients and 7.1%
(3.1% Grade .gtoreq.3) of everolimus-treated patients. Patients'
blood pressure should be monitored prior to initiation and
regularly during CABOMETYX.RTM. treatment. CABOMETYX.RTM. should be
withheld for hypertension that is not adequately controlled with
medical management; when controlled, CABOMETYX.RTM. should be
resumed at a reduced dose. CABOMETYX.RTM. should be discontinued
for severe hypertension that cannot be controlled with
anti-hypertensive therapy. CABOMETYX.RTM. should be discontinued if
there is evidence of hypertensive crisis or severe hypertension
despite optimal medical management.
[0327] Diarrhea occurred in 74% of patients treated with
CABOMETYX.RTM. and was Grade 3 in 11% of patients. CABOMETYX.RTM.
should be withheld in patients who develop intolerable Grade 2
diarrhea or Grade 3-4 diarrhea that cannot be managed with standard
antidiarrheal treatments until improvement to Grade 1; upon
improvement to Grade 1, CABOMETYX.RTM. should be resumed at a
reduced dose. Dose modification due to diarrhea occurred in 26% of
patients.
[0328] Palmar-plantar erythrodysesthesia syndrome (PPES) occurred
in 42% of patients treated with CABOMETYX.RTM. and was Grade 3 in
8.2% of patients. CABOMETYX.RTM. should be withheld in patients who
develop intolerable Grade 2 PPES or Grade 3 PPES until improvement
to Grade 1; upon improvement to Grade 1, CABOMETYX.RTM. should be
resumed at a reduced dose. Dose modification due to PPES occurred
in 16% of patients. Reversible Posterior Leukoencephalopathy
Syndrome (RPLS), a syndrome of subcortical vasogenic edema
diagnosed by characteristic finding on MRI, occurred in the
cabozantinib clinical program. An evaluation for RPLS should be
performed in any patient presenting with seizures, headache, visual
disturbances, confusion or altered mental function. CABOMETYX.RTM.
should be discontinued in patients who develop RPLS.
[0329] Based on data from animal studies and its mechanism of
action, CABOMETYX.RTM. can cause fetal harm when administered to a
pregnant woman. Cabozantinib administration to pregnant animals
during organogenesis resulted in embryolethality at exposures below
those occurring clinically at the recommended dose, and in
increased incidences of skeletal variations in rats and visceral
variations and malformations in rabbits. Pregnant women should be
advised of the potential risk to a fetus. Females of reproductive
potential should be advised to use effective contraception during
treatment with CABOMETYX.RTM. and for 4 months after the last
dose.
Adverse Reactions
[0330] Adverse Reactions are summarized in Tables A and B. The
following serious adverse reactions are discussed elsewhere in the
application: hemorrhage; GI perforations and fistulas; thrombotic
events; hypertension and hypertensive; crisis diarrhea;
palmar-plantar erythrodysesthesia syndrome; reversible posterior
leukoencephalopathy syndrome.
Clinical Trial Experience
[0331] Because clinical trials are conducted under widely varying
conditions, adverse reaction rates observed in the clinical trials
of a drug cannot be directly compared to rates in the clinical
trials of another drug and may not reflect the rates observed in
practice.
[0332] The safety of CABOMETYX.RTM. was evaluated in Study 1, a
randomized, open-label trial in which 331 patients with advanced
renal cell carcinoma received 60 mg CABOMETYX.RTM. and 322 patients
received 10 mg everolimus administered daily until the patient no
longer experienced clinical benefit or experienced intolerable
toxicity. The median duration of treatment was 7.6 months (range
0.3-20.5) for patients receiving CABOMETYX.RTM. and 4.4 months
(range 0.21-18.9) for patients receiving everolimus.
[0333] Adverse reactions which occurred in .gtoreq.25% of
CABOMETYX.RTM.-treated patients included, in order of decreasing
frequency: diarrhea, fatigue, nausea, decreased appetite,
palmar-plantar erythrodysesthesia syndrome (PPES), hypertension,
vomiting, weight decreased, and constipation. Grade 3-4 adverse
reactions which occurred in .gtoreq.5% of patients were fatigue,
diarrhea, hypertension, palmar-plantar erythrodysesthesia syndrome,
and anemia.
[0334] The most common laboratory abnormalities in
CABOMETYX.RTM.-treated patients (.gtoreq.25%) were:
hypophosphatemia, hypomagnesemia, increased lipase, hyponatremia,
AST increased, and ALT increased.
[0335] The dose was reduced in 60% of patients receiving
CABOMETYX.RTM. and in 24% of patients receiving everolimus. Twenty
percent (20%) of patients received 20 mg CABOMETYX.RTM. as their
lowest dose. The most frequent adverse reactions leading to dose
reduction in patients treated with CABOMETYX.RTM. were: diarrhea,
PPES, fatigue, and hypertension. Adverse reactions led to study
treatment being held in 70% patients receiving CABOMETYX.RTM. and
in 59% patients receiving everolimus. Adverse reactions led to
study treatment discontinuation in 10% of patients receiving
CABOMETYX.RTM. and in 10% of patients receiving everolimus. The
most frequent adverse reactions leading to permanent
discontinuation in patients treated with CABOMETYX.RTM. were
decreased appetite (2%) and fatigue (1%).
TABLE-US-00002 TABLE A Adverse Reactions Occurring in .gtoreq.10%
Patients Who Received CABOMETYX CABOMETYX Everolimus (n = 331)
.sup.1 (n = 322) All Grade All Grade Grades.sup.2 3-4 Grades.sup.2
3-4 Adverse Reaction Percentage (%) of Patients Gastrointestinal
Disorders Diarrhea 74 11 28 2 Nausea 50 4 28 <1 Vomiting 32 2 14
<1 Stomatitis 22 2 24 2 Constipation 25 <1 19 <1 Abdominal
pain .sup.3 23 4 13 2 Dyspepsia 12 <1 5 0 General Disorders and
Administration Site Conditions Fatigue 56 9 47 7 Mucosal
inflammation 19 <1 23 3 Asthenia 19 4 16 2 Metabolism and
Nutrition Disorders Decreased appetite 46 3 34 <1 Skin and
Subcutaneous Tissue Disorders Palmar-plantar erythrodysesthesia 42
8 6 <1 syndrome Rash .sup.4 23 <1 43 <1 Dry skin 11 0 10 0
Vascular Disorders Hypertension .sup.5 39 16 8 3 Investigations
Weight decreased 31 2 12 0 Nervous System Disorders Dysgeusia 24 0
9 0 Headache 11 <1 12 <1 Dizziness 11 0 7 0 Endocrine
Disorders Hypothyroidism 21 0 <1 <1 Respiratory, Thoracic,
and Mediastinal Disorders Dysphonia 20 <1 4 0 Dyspnea 19 3 29 4
Cough 18 <1 33 <1 Blood and Lymphatic Disorders Anemia 17 5
38 16 Musculoskeletal and Connective Tissue Disorders Pain in
extremity 14 1 8 <1 Muscle spasms 13 0 5 0 Arthralgia 11 <1
14 1 Renal and Urinary Disorders Proteinuria 12 2 9 <1 .sup.1
One subject randomized to everolimus received cabozantinib.
.sup.2National Cancer Institute Common Terminology Criteria for
Adverse Events Version 4.0 .sup.3 Includes PT terms abdominal pain,
abdominal pain upper, and abdominal pain lower .sup.4 Includes PT
terms rash, rash erythematous, rash follicular, rash macular, rash
papular, rash pustular, rash vesicular, genital rash, intermittent
leg rash, rash on scrotum and penis, rash maculo-papular, rash
pruritic, contact dermatitis, dermatitis acneiform .sup.5 Includes
PT terms hypertension, blood pressure increased, hypertensive
crisis, blood pressure fluctuation
[0336] Other clinically important adverse reactions (all grades)
that were reported in <10% of patients treated with
CABOMETYX.RTM. included: wound complications (2%), convulsion
(<1%), pancreatitis (<1%), osteonecrosis of the jaw (<1%),
and hepatitis cholestatic (<1%)
TABLE-US-00003 TABLE B Laboratory Abnormalities Occurring in
.gtoreq.25% Patients Who Received CABOMETYX CABOMETYX Everolimus (n
= 331) (n = 322) All Grade 3- All Test Grades 4 Grades Grade 3-4
Chemistry AST increased 74 3 40 <1 ALT increased 68 3 32 <1
Creatinine increased 58 <1 71 0 Triglycerides increased 53 4 73
13 Hypophosphatemia 48 8 36 5 Hyperglycemia 37 2 59 8
Hypoalbuminemia 36 2 28 <1 ALP increased 35 2 29 1
Hypomagnesemia 31 7 4 <1 Hyponatremia 30 8 26 6 GGT increased 27
5 43 9 Hematology White blood cells decreased 35 <1 31 <1
Absolute neutrophil count decreased 31 2 17 <1 Hemoglobin
decreased 31 4 71 17 Lymphocytes decreased 25 7 39 12 Platelets
decreased 25 <1 27 <1 ALP, alkaline phosphatase; ALT, alanine
aminotransferase; AST, aspartate aminotransferase; GGT, gamma
glutamyl transferase. National Cancer Institute Common Terminology
Criteria for Adverse Events, Version 4.0
Drug Interactions
[0337] Drug interactions are summarized in Table C.
TABLE-US-00004 TABLE C Clinically Significant Drug Interactions
Involving Drugs that Affect Cabozantinib Strong CYP3A4 Inhibitors
Clinical Concomitant use of CABOMETYX .RTM. with a strong
Implications: CYP3A4 inhibitor increased the exposure of
cabozantinib compared to the use of CABOMETYX .RTM. alone.
Increased cabozantinib exposure may increase the risk of
exposure-related toxicity. Prevention or Reduce the dosage of
CABOMETYX .RTM. if concomitant Management: use with strong CYP3A4
inhibitors cannot be avoided. Examples: Boceprevir, clarithromycin,
conivaptan, grapefruit juice.sup.a, indinavir, itraconazole,
ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir,
posaconazole, ritonavir, saquinavir, telithromycin, and
voriconazole Strong CYP3A4 Inducers Clinical Concomitant use of
CABOMETYX .RTM. with a strong Implications: CYP3A4 inducer
decreased the exposure of cabozantinib compared to the use of
CABOMETYX .RTM. alone. Decreased cabozantinib exposure may lead to
reduced efficacy. Prevention or Increase the dosage of CABOMETYX
.RTM. if concomitant Management: use with strong CYP3A4 inducers
cannot be avoided. Examples: Rifampin, phenytoin, carbamazepine,
phenobarbital, rifabutin, rifapentine, and St. John's Wort.sup.b
.sup.aThe effect of grapefruit juice varies widely among brands and
is concentration-, dose-, and preparation-dependent. Studies have
shown that it can be classified as a "strong CYP3A inhibitor" when
a certain preparation was used (e.g., high dose, double strength)
or as a "moderate CYP3A inhibitor" when another preparation was
used (e.g., low dose, single strength). .sup.bThe effect of St.
John's Wort varies widely and is preparation-dependent
Use in Specific Populations
[0338] Pregnancy
[0339] Based on findings from animal studies and its mechanism of
action, CABOMETYX.RTM. can cause fetal harm when administered to a
pregnant woman.
[0340] There are no available data in pregnant women to inform the
drug-associated risk. In animal developmental and reproductive
toxicology studies administration of cabozantinib to pregnant rats
and rabbits during organogenesis resulted in embryofetal lethality
and structural anomalies at exposures that were below those
occurring clinically at the recommended dose. Pregnant women or
women of childbearing potential should be advised of the potential
hazard to a fetus.
[0341] The estimated background risk of major birth defects and
miscarriage for the indicated population is unknown. In the U.S.
general population, the estimated background risk of major birth
defects and miscarriage in clinically recognized pregnancies is
2-4% and 15-20%, respectively.
[0342] In an embryo-fetal development study in pregnant rats, daily
oral administration of cabozantinib throughout organogenesis caused
increased embryo-fetal lethality compared to controls at a dose of
0.03 mg/kg (approximately 0.12-fold of human AUC at the recommended
dose). Findings included delayed ossification and skeletal
variations at a dose of 0.1 mg/kg/day (approximately 0.04-fold of
human AUC at the recommended dose).
[0343] In pregnant rabbits, daily oral administration of
cabozantinib throughout organogenesis resulted in findings of
visceral malformations and variations including reduced spleen size
and missing lung lobe at 3 mg/kg (approximately 1.1-fold of the
human AUC at the recommended dose).
[0344] In a pre- and postnatal study in rats, cabozantinib was
administered orally from gestation day 10 through postnatal day 20.
Cabozantinib did not produce adverse maternal toxicity or affect
pregnancy, parturition or lactation of female rats, and did not
affect the survival, growth or postnatal development of the
offspring at doses up to 0.3 mg/kg/day (0.05-fold of the maximum
recommended clinical dose).
[0345] Lactation
[0346] There is no information regarding the presence of
cabozantinib or its metabolites in human milk, or their effects on
the breastfed infant, or milk production. Because of the potential
for serious adverse reactions in a breastfed infant from CABOMETYX,
a lactating woman should be advised not to breastfeed during
treatment with CABOMETYX.RTM. and for 4 months after the final
dose.
[0347] Females and Males of Reproductive Potential
[0348] CABOMETYX.RTM. can cause fetal harm when administered to a
pregnant woman.
[0349] Females of reproductive potential should be advised to use
effective contraception during treatment with CABOMETYX.RTM. and
for 4 months after the final dose.
[0350] Infertility
[0351] Based on findings in animals, CABOMETYX.RTM. may impair
fertility in females and males of reproductive potential.
[0352] Pediatric Use
[0353] The safety and effectiveness of CABOMETYX.RTM. in pediatric
patients have not been studied.
[0354] Juvenile Animal Data
[0355] Juvenile rats were administered cabozantinib daily at doses
of 1 or 2 mg/kg/day from Postnatal Day 12 (comparable to less than
2 years in humans) through Postnatal Day 35 or 70. Mortalities
occurred at doses equal and greater than 1 mg/kg/day (approximately
0.16 times the clinical dose of 60 mg/day based on body surface
area). Hypoactivity was observed at both doses tested on Postnatal
Day 22. Targets were generally similar to those seen in adult
animals, occurred at both doses, and included the kidney
(nephropathy, glomerulonephritis), reproductive organs,
gastrointestinal tract (cystic dilatation and hyperplasia in
Brunner's gland and inflammation of duodenum; and epithelial
hyperplasia of colon and cecum), bone marrow (hypocellularity and
lymphoid depletion), and liver. Tooth abnormalities and whitening
as well as effects on bones including reduced bone mineral content
and density, physeal hypertrophy, and decreased cortical bone also
occurred at all dose levels. Recovery was not assessed at the 2
mg/kg dose level (approximately 0.32 times the clinical dose of 60
mg based on body surface area) due to high levels of mortality. At
the low dose level, effects on bone parameters were partially
resolved but effects on the kidney and epididymis/testis persisted
after treatment ceased.
[0356] Geriatric Use
[0357] In the Phase 3 study, 41% of RCC patients treated with
CABOMETYX.RTM. were age 65 years and older, and 8% were age 75 and
older. No differences in safety or efficacy were observed between
older and younger patients.
[0358] Hepatic Impairment
[0359] Increased exposure to cabozantinib has been observed in
patients with mild to moderate hepatic impairment. The
CABOMETYX.RTM. dose should be reduced in patients with mild
(Child-Pugh score (C-P) A) or moderate (C-P B) hepatic impairment.
CABOMETYX.RTM. is not recommended for use in patients with severe
hepatic impairment.
[0360] Renal Impairment
[0361] Dosage adjustment is not required in patients with mild or
moderate renal impairment. There is no experience with
CABOMETYX.RTM. in patients with severe renal impairment.
[0362] Overdosage
[0363] One case of overdosage was reported in the cabozantinib
clinical program; a patient inadvertently took twice the intended
dose (200 mg daily) of another formulation of cabozantinib product
for nine days. The patient suffered Grade 3 memory impairment,
Grade 3 mental status changes, Grade 3 cognitive disturbance, Grade
2 weight loss, and Grade 1 increase in BUN. The extent of recovery
was not documented.
Description
[0364] CABOMETYX.RTM. comprises the (S)-malate salt of
cabozantinib, a kinase inhibitor. Cabozantinib (S)-malate is
described chemically as
N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N'-(4-fluorophenyl)cyclopropa-
ne-1,1-dicarboxamide, (2S)-hydroxybutanedioate. The molecular
formula is C.sub.28H.sub.24FN.sub.3O.sub.5.C.sub.4H.sub.6O.sub.5
and the molecular weight is 635.6 Daltons as malate salt. The
chemical structure of cabozantinib (S)-malate salt is:
##STR00004##
Cabozantinib (S)-malate salt is an white to off-white solid that is
practically insoluble in aqueous media.
[0365] CABOMETYX.RTM. (cabozantinib) tablets are supplied as
film-coated tablets containing 20 mg, 40 mg, or 60 mg of
cabozantinib, which is equivalent to 25 mg, 51 mg, or 76 mg of
cabozantinib (S)-malate, respectively. CABOMETYX.RTM. also contains
the following inactive ingredients: microcrystalline cellulose,
lactose anhydrous, hydroxypropyl cellulose, croscarmellose sodium,
colloidal silicon dioxide, and magnesium stearate.
[0366] The film coating contains hypromellose, titanium dioxide,
triacetin, and iron oxide yellow.
Clinical Pharmacology
[0367] Mechanism of Action
[0368] In vitro biochemical and/or cellular assays have shown that
cabozantinib inhibits the tyrosine kinase activity of MET, VEGFR-1,
-2 and -3, AXL, RET, ROS1, TYRO3, MER, KIT, TRKB, FLT-3, and TIE-2.
These receptor tyrosine kinases are involved in both normal
cellular function and pathologic processes such as oncogenesis,
metastasis, tumor angiogenesis, drug resistance, and maintenance of
the tumor microenvironment.
[0369] Pharmacodynamics
[0370] The exposure-response or -safety relationship for
cabozantinib is unknown.
[0371] Cardiac Electrophysiology
[0372] The effect of orally administered cabozantinib on QTc
interval was evaluated in a randomized, double-blinded,
placebo-controlled study in patients with medullary thyroid cancer
administered a dose of 140 mg. A mean increase in QTcF of 10-15 ms
was observed at 4 weeks after initiating cabozantinib, A
concentration-QTc relationship could not be definitively
established. Changes in cardiac wave form morphology or new rhythms
were not observed. No cabozantinib-treated patients in this study
had a confirmed QTcF>500 ms nor did any cabozantinib-treated
patients in the RCC study (at a dose of 60 mg).
[0373] Pharmacokinetics
[0374] Repeat daily dosing of cabozantinib at 140 mg for 19 days
resulted in 4- to 5-fold mean cabozantinib accumulation (based on
AUC) compared to a single dose administration; steady state was
achieved by Day 15.
[0375] Absorption
[0376] Following oral administration of cabozantinib, median time
to peak cabozantinib plasma concentrations (T.sub.max) ranged from
2 to 3 hours post-dose.
[0377] A 19% increase in the C.sub.max of the tablet formulation
(CABOMETYX) compared to the capsule formulation (COMETRIQ.RTM.) was
observed following a single 140 mg dose. A less than 10% difference
in the AUC was observed between cabozantinib tablet (CABOMETYX) and
capsule (COMETRIQ) formulations.
[0378] Cabozantinib C.sub.max and AUC values increased by 41% and
57%, respectively, following a high-fat meal relative to fasted
conditions in healthy subjects administered a single 140 mg oral
dose of an investigational cabozantinib capsule formulation.
[0379] Distribution
[0380] The oral volume of distribution (VJF) of cabozantinib is
approximately 319 L. Cabozantinib is highly protein bound in human
plasma (.gtoreq.99.7%).
[0381] Elimination
[0382] The predicted terminal half-life is approximately 99 hours
and the clearance (CL/F) at steady-state is estimated to be 2.2
L/hr.
[0383] Metabolism
[0384] Cabozantinib is a substrate of CYP3A4 in vitro.
[0385] Excretion
[0386] Approximately 81% of the total administered radioactivity
was recovered within a 48-day collection period following a single
140 mg dose of an investigational .sup.14C-cabozantinib formulation
in healthy subjects. Approximately 54% was recovered in feces and
27% in urine. Unchanged cabozantinib accounted for 43% of the total
radioactivity in feces and was not detectable in urine following a
72 hour collection.
[0387] Specific Populations
[0388] The following patient characteristics did not result in a
clinically relevant difference in the pharmacokinetics of
cabozantinib: age (32-86 years), sex, race (Whites and non-Whites),
or mild to moderate renal impairment (eGFR greater than or equal to
30 mL/min/1.73 m.sup.2 as estimated by MDRD (modification of diet
in renal disease equation)). The pharmacokinetics of cabozantinib
is unknown in patients with worse than moderate renal impairment
(eGFR less than 29 mL/min/1.73 m.sup.2) as estimated by MDRD
equation or renal impairment requiring dialysis.
[0389] Hepatic Impairment
[0390] Cabozantinib exposure (AUC.sub.0-inf) increased by 81% and
63%, respectively, in patients with mild (C-P A) and moderate (C-P
B) hepatic impairment. Patients with severe hepatic impairment have
not been studied.
[0391] Pediatric Population
[0392] The pharmacokinetics of cabozantinib has not been studied in
the pediatric population.
[0393] Drug Interactions
[0394] CYP3A4 Inhibition on Cabozantinib: Administration of a
strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days) to
healthy subjects increased single-dose plasma cabozantinib exposure
(AUC.sub.0-inf) by 38%.
[0395] CYP3A4 Induction on Cabozantinib: Administration of a strong
CYP3A4 inducer, rifampin (600 mg daily for 31 days) to healthy
subjects decreased single-dose plasma cabozantinib exposure
(AUC.sub.0-inf) by 77%.
[0396] Cabozantinib on CYP2C8 substrates: No clinically-significant
effect on single-dose rosiglitazone (a CYP2C8 substrate) plasma
exposure (C.sub.max and AUC) was observed when co-administered with
cabozantinib at steady-state plasma concentrations (.gtoreq.100
mg/day daily for a minimum of 21 days) in patients with solid
tumors.
[0397] Gastric pH modifying agents on Cabozantinib: No
clinically-significant effect on plasma cabozantinib exposure (AUC)
was observed following co-administration of the proton pump
inhibitor (PPI) esomeprazole (40 mg daily for 6 days) with a single
dose of 100 mg cabozantinib to healthy volunteers.
In vitro Studies
[0398] Metabolic Pathways
[0399] Inhibition of CYP3A4 reduced the formation of the oxidative
metabolite by >80%. Inhibition of CYP2C9 had a minimal effect on
cabozantinib metabolite formation (i.e., a <20% reduction).
Inhibition of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2D6 and
CYP2E1 had no effect on cabozantinib metabolite formation.
[0400] Although cabozantinib is an inhibitor of CYP2C8 in vitro, a
clinical study of this potential interaction concluded that
concurrent use did not result in a clinically relevant effect on
CYP2C8 substrate exposure. Given this finding, other less sensitive
substrates of pathways affected by cabozantinib in vitro (i.e.,
CYP2C9, CYP2C19, and CYP3A4) were not evaluated in a clinical study
because, although a clinically relevant exposure effect cannot be
ruled out, it is unlikely. Cabozantinib does not inhibit CYP1A2 and
CYP2D6 isozymes in vitro.
[0401] Cabozantinib is an inducer of CYP1A1 mRNA; however, the
clinical relevance of this finding is unknown. Cabozantinib does
not induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or CYP3A4.
[0402] Drug Transporter Systems
[0403] Cabozantinib is an inhibitor, but not a substrate, of P-gp
transport activities and has the potential to increase plasma
concentrations of co-administered substrates of P-gp. The clinical
relevance of this finding is unknown. Cabozantinib is a substrate
of MRP2 in vitro and MRP2 inhibitors have the potential to increase
plasma concentrations of cabozantinib. The clinical relevance of
this finding is unknown.
Nonclinical Toxicology
[0404] Carcinogenesis, Mutagenesis, Impairment of Fertility
[0405] Cabozantinib was not carcinogenic in a 26-week
carcinogenicity study in rasH2 transgenic mice. Cabozantinib was
not mutagenic in vitro in the bacterial reverse mutation (Ames)
assay and was not clastogenic in both the in vitro cytogenetic
assay using human lymphocytes or in the in vivo mouse micronucleus
assay. Based on nonclinical findings, male and female fertility may
be impaired by treatment with CABOMETYX.RTM.. In a fertility study
in which cabozantinib was administered to male and female rats at
doses of 1, 2.5, and 5 mg/kg/day, male fertility was significantly
compromised at doses equal to or greater than 2.5 mg/kg/day
(approximately 13-fold of human AUC at the recommended dose), with
a decrease in sperm counts and reproductive organ weights. In
females, fertility was significantly reduced at doses equal to or
greater than 1 mg/kg/day (5-fold of human AUC at the recommended
dose) with a significant decrease in the number of live embryos and
a significant increase in pre- and post-implantation losses.
[0406] Observations effects on reproductive tract tissues in
general toxicology studies were supportive effects noted in the
dedicated fertility study and included hypospermia and absence of
corpora lutea in male and female dogs in a 6-month repeat dose
study at plasma exposures (AUC) approximately 0.5-fold (males) and
<0.1-fold (females) of those expected in humans at the
recommended dose. In addition, female rats administered 5 mg/kg/day
for 14 days (approximately 9-fold of human AUC at the recommended
dose) exhibited ovarian necrosis.
EMBODIMENTS
[0407] The following embodiments are included in the invention.
[0408] Embodiment 1. A method of treating advanced renal cell
carcinoma with or without bone metastases in a human patient who
has received prior anti-angiogenic therapy, comprising
administering to the patient an amount of cabozantinib or a
pharmaceutically acceptable salt thereof, wherein progression-free
survival (PFS) and one or both of overall survival (OS) and
objective response rate (ORR) are extended as compared to patients
who have received prior anti-angiogenic therapy, wherein the prior
anti-angiogenic therapy is selected from the group consisting of
axitinib, pazopanib, sorafenib, sunitinib, everolimus,
temsirolimus, bevacizumab, interleukins, interferon-.alpha.,
peginterferon, nivolumab, AMP-514, and atezolizumab.
[0409] Embodiment 2. The method of embodiment 1, wherein the
cabozantinib is administered as cabozantinib (S)-malate.
[0410] Embodiment 3. The method of any of embodiments 1-2, wherein
cabozantinib (S)-malate is administered in an amount sufficient to
achieve a median time to peak plasma concentration (Tmax) of from
approximately 2 to 5 hours post-dose; and a Cmax of 200 to 500
ng/mL.
[0411] Embodiment 4. The method of any of embodiments 1-3, wherein
the prior antiangiogenic therapy is selected from the group
consisting of axitinib, pazopanib, sorafenib, sunitinib,
everolimus, temsirolimus, bevacizumab, nivolumab, AMP-514, and
atezolizumab.
[0412] Embodiment 5. The method of any of embodiments 1-4, wherein
the prior anti-angiogenic therapy is everolimus.
[0413] Embodiment 6. The method of any of embodiments 1-5, wherein
cabozantinib (S)-malate is administered as a tablet comprising
cabozantinib (S)-malate, microcrystalline cellulose, anhydrous
lactose, hydroxypropyl cellulose, croscarmellose sodium, colloidal
silicon dioxide magenisum stearate, and film coating comprising
hypromellose, titanium dioxide, triacetin, and iron oxide
yellow.
[0414] Embodiment 7. The method of any of embodiments 1-6, wherein
the cabozantinib (S)-malate is administered as a tablet formulation
comprising approximately:
[0415] 30-32 percent by weight of cabozantinib, (S)-malate
salt;
[0416] 38-40 percent by weight of microcrystalline cellulose;
[0417] 18-22 percent by weight of lactose;
[0418] 2-4 percent by weight of hydroxypropyl cellulose;
[0419] 4-8 percent by weight of croscarmellose sodium;
[0420] 0.2-0.6 percent by weight of colloidal silicon dioxide;
[0421] 0.5-1 percent by weight of magnesium stearate; and further
comprising: a film coating material comprising hypromellose,
titanium dioxide, triacetin, and iron oxide yellow.
[0422] Embodiment 8. The method of any of embodiments 1-7, wherein
the cabozantinib (S)-malate is administered as a tablet formulation
comprising approximately (% w/w):
[0423] 31-32 percent by weight of cabozantinib, (S)-malate
salt;
[0424] 39-40 percent by weight of microcrystalline cellulose;
[0425] 19-20 percent by weight of lactose;
[0426] 2.5-3.5 percent by weight of hydroxypropyl cellulose;
[0427] 5.5-6.5 percent by weight of croscarmellose sodium;
[0428] 0.25-0.35 percent by weight of colloidal silicon
dioxide;
[0429] 0.7-0.8 percent by weight of magnesium stearate; and further
comprising:
[0430] 3.9-4.1 percent by weight of a film coating material
comprising hypromellose, titanium dioxide, triacetin, and iron
oxide yellow.
[0431] Embodiment 9. The method of any of embodiments 1-8, wherein
cabozantinib (S)-malate is administered as a tablet formulation
containing 20, 40, or 60 mg of cabozantinib (FBE).
[0432] Embodiment 10. The method of any of embodiments 1-9, wherein
cabozantinib (S)-malate is administered as a tablet formulation
selected from the group consisting of:
TABLE-US-00005 Theoretical Quantity (mg/unit dose) Ingredient 20-mg
Tablet* 40-mg Tablet* 60-mg Tablet* Cabozantinib (S)-malate 25.34
50.69 76.03 Microcrystalline Cellulose, PH-102 31.08 62.16 93.24
Lactose Anhydrous, 60M 15.54 31.07 46.61 Hydroxypropyl Cellulose,
EXF 2.400 4.800 7.200 Croscarmellose Sodium 4.800 9.600 14.40
Colloidal Silicon Dioxide 0.2400 0.4800 0.7200 Magnesium Stearate
(Non-Bovine) 0.6000 1.200 1.800 Opadry .RTM. Yellow (03K92254)
3.200 6.400 9.600 Total tablet weight 83.20 166.4 249.6 *Free Base
Equivalent (FBE)
[0433] Embodiment 11. The method of any of embodiments 1-10,
wherein the cabozantinib (S)-malate is administered once daily.
[0434] Embodiment 12. The method of any of embodiments 1-11,
wherein the amount of cabozantinib that is administered once daily
is 60 mg FBE.
[0435] Embodiment 13. The method of any of embodiments 1-12,
wherein the amount of cabozantinib (S)-malate is sufficient to
achieve a median time to peak plasma concentration (Tmax) from 3.2
to 3.8 hours post-dose; and a mean Cmax of 310 to 350 ng/mL.
[0436] Embodiment 14. The method of any of embodiments 1-13,
wherein the overall survival of the patient is extended as compared
to patients taking everolimus.
[0437] Embodiment 15. The method of any of embodiments 1-14,
wherein the objective response rate of the patient is extended as
compared to patients taking everolimus.
[0438] Embodiment 16. The method of any of embodiments 1-15,
wherein both the overall survival and the objective response rate
of the patient is extended as compared to patients taking
everolimus.
[0439] Embodiment 17. The method of any of embodiments 1-15 wherein
an amount of cabozantinib (S)-malate is sufficient to achieve one,
two, three, four, five, six, seven, or eight effects selected from
the group consisting of:
[0440] a median time to peak plasma concentration (Tmax) from 2 to
5 hours post-dose;
[0441] a Cmax of 200 to 500 ng/mL;
[0442] an AUC.sub.0-24 of 2500 to 5200 ng*h/mL;
[0443] an AUC.sub.0-t of 18,000 to 42,000 ng*h/mL;
[0444] an AUC.sub.0-.infin. of 19,000 to 45,000 ng*h/mL;
[0445] an oral volume distribution (Vz/F) of 100 to 600 L;
[0446] a terminal half-life of 90 to 135 h; and
[0447] a clearance at steady state (CL/F) of 0.7 to 3.9 L/h;
wherein the cabozantinib (S)-malate is administered as a tablet
formulation comprising approximately (% w/w):
[0448] 31-32 percent by weight of cabozantinib, (S)-malate
salt;
[0449] 39-40 percent by weight of microcrystalline cellulose;
[0450] 19-20 percent by weight of lactose;
[0451] 2.5-3.5 percent by weight of hydroxypropyl cellulose;
[0452] 5.5-6.5 percent by weight of croscarmellose sodium;
[0453] 0.25-0.35 percent by weight of colloidal silicon
dioxide;
[0454] 0.7-0.8 percent by weight of magnesium stearate; and further
comprising:
[0455] 3.9-4.1 percent by weight of a film coating material
comprising hypromellose, titanium dioxide, triacetin, and iron
oxide yellow.
[0456] Embodiment 18. The method of embodiment 17, wherein
cabozantinib (S)-malate is administered as a tablet formulation
containing 20, 40, or 60 mg of cabozantinib.
[0457] Embodiment 19. The method of any of embodiments 17-18,
wherein cabozantinib (S)-malate is administered as a tablet
formulation selected from the group consisting of:
TABLE-US-00006 Theoretical Quantity (mg/unit dose) Ingredient 20-mg
Tablet* 40-mg Tablet* 60-mg Tablet* Cabozantinib (S)-malate 25.34
50.69 76.03 Microcrystalline Cellulose, PH-102 31.08 62.16 93.24
Lactose Anhydrous, 60M 15.54 31.07 46.61 Hydroxypropyl Cellulose,
EXF 2.400 4.800 7.200 Croscarmellose Sodium 4.800 9.600 14.40
Colloidal Silicon Dioxide 0.2400 0.4800 0.7200 Magnesium Stearate
(Non-Bovine) 0.6000 1.200 1.800 Opadry .RTM. Yellow (03K92254)
3.200 6.400 9.600 Total tablet weight 83.20 166.4 249.6 *Free Base
Equivalent (FBE)
[0458] Embodiment 20. The method of any of embodiments 1-19,
wherein the cabozantinib (S)-malate is administered in an amount
sufficient to achieve one, two, three, four, five, six, seven, or
eight effects selected from the group consisting of: a median time
to peak plasma concentration (Tmax) from 2 to 5 hours
post-dose;
[0459] a Cmax of 200 to 500 ng/mL;
[0460] an AUC.sub.0-24 of 2500 to 5200 ng*h/mL;
[0461] an AUC.sub.0-t of 18,000 to 42,000 ng*h/mL;
[0462] an AUC.sub.0-.infin. of 19,000 to 45,000 ng*h/mL;
[0463] an oral volume distribution (Vz/F) of 100 to 600 L;
[0464] a terminal half-life of 90 to 135 h; and
[0465] a clearance at steady state (CL/F) of 0.7 to 3.9 L/h
[0466] Embodiment 21 The method of any of embodiments 1-20, wherein
the cabozantinib (S)-malate is administered in an amount sufficient
to achieve one, two, three, four, five, six, seven, or eight
effects selected from the group consisting of:
[0467] a median time to peak plasma concentration (Tmax) from 2.5
to 4.5 hours post-dose;
[0468] a Cmax of 250 to 450 ng/mL;
[0469] an AUC.sub.0-24 of 3000 to 4700 ng*h/mL;
[0470] an AUC.sub.0-t of 23,000 to 37,000 ng*h/mL;
[0471] an AUC.sub.0-.infin. of 24,000 to 40,000 ng*h/mL;
[0472] an oral volume distribution (Vz/F) of 150 to 550 L;
[0473] a terminal half-life of 100 to 125 h; and
[0474] a clearance at steady state (CL/F) of 1.2 to 3.2 L/h.
[0475] Embodiment 22. The method of any of embodiments 1-21,
wherein the cabozantinib (S)-malate is administered in an amount
sufficient to achieve one, two, three, four, five, six, seven, or
eight effects selected from the group consisting of:
[0476] a median time to peak plasma concentration (Tmax) from 3 to
4 hours post-dose;
[0477] a Cmax of 300 to 400 ng/mL;
[0478] an AUC.sub.0-24 of 3500 to 4200 ng*h/mL;
[0479] an AUC.sub.0-t of 28,000 to 32,000 ng*h/mL;
[0480] an AUC.sub.0-.infin. of 29,000 to 35,000 ng*h/mL;
[0481] an oral volume distribution (Vz/F) of 200 to 500 L;
[0482] a terminal half-life of 110 to 115 h; and
[0483] a clearance at steady state (CL/F) of 1.2 to 3.2
[0484] Embodiment 23. The method of any of embodiments 1-19,
wherein the cabozantinib (S)-malate is administered in an amount
sufficient to achieve one, two, three, four, five, six, seven, or
eight effects selected from the group consisting of:
[0485] a median time to peak plasma concentration (Tmax) from 3.2
to 3.8 hours post-dose;
[0486] a Cmax of 310 to 350 ng/mL;
[0487] an AUC.sub.0-24 of 3700 to 4000 ng*h/mL;
[0488] an AUC.sub.0-t of 29,000 to 30,000 ng*h/mL;
[0489] an AUC.sub.0-.infin. of 30,000 to 33,000 ng*h/mL;
[0490] an oral volume distribution (Vz/F) of 300 to 400 L;
[0491] a terminal half-life of 110 to 114 h; and
[0492] a clearance at steady state (CL/F) of 2 to 3.
[0493] Embodiment 24. A method of treating advanced renal cell
carcinoma in human patients who have received prior anti-angiogenic
therapy, comprising administering to the patient cabozantinib or a
pharmaceutically acceptable salt thereof, wherein the overall
survival of the patients are extended as compared to the median
overall survival of patients who have received prior
anti-angiogenic therapy, wherein the prior anti-angiogenic therapy
is selected from the group consisting of axitinib, pazopanib,
sorafenib, sunitinib, everolimus, temsirolimus, bevacizumab,
interleukins, interferon-.alpha., peginterferon, nivolumab,
AMP-514, and atezolizumab.
[0494] Embodiment 25. The method of embodiment 24, wherein the
cabozanitinib is administered as cabozantinib (S)-malate.
[0495] Embodiment 26. The method of any of embodiments 24-25,
wherein the overall survival is extended for patients taking
cabozantinib (S)-malate as compared to patients who have received
axitinib, pazopanib, sorafenib, sunitinib, everolimus,
temsirolimus, bevacizumab, nivolumab, AMP-514, and atezolizumab as
the prior anti-angiogenic therapy.
[0496] Embodiment 27. The method of any of embodiments 24-26,
wherein the overall survival is extended for patients taking
cabozantinib (S)-malate as compared to patients who have received
nivolumab therapy.
[0497] Embodiment 28. The method of any of embodiments 24-27,
wherein the patients are selected from the group consisting of
patients with favorable, intermediate, and poor prognoses on the
Memorial Sloan Kettering Cancer Center (MSKCC) Risk Group, patients
with bone metastases, patients with visceral metastases, and
patients with visceral and bone metastases.
[0498] Embodiment 29. The method of any of embodiments 24-28,
wherein one or both of progression-free survival (PFS) and
objective response rate are also extended over patients who have
received prior anti-angiogenic therapy.
[0499] Embodiment 30. The method of any of embodiments 24-29
wherein the cabozantinib (S)-malate is administered in an amount
sufficient to achieve to achieve a median time to peak plasma
concentration (Tmax) from 2 to 5 hours post-dose; and a mean Cmax
of 200 to 500 ng/mL; wherein: the overall survival of the patient
is extended as compared to a the median overall survival of
patients taking who have received prior anti-angiogenic therapy;
and wherein one or both of progression-free survival (PFS) and
objective response rate are also extended over patients taking who
have received prior anti-angiogenic therapy.
[0500] Embodiment 31. The method of any of embodiments 24-30,
wherein the prior antiangiogenic therapy is selected from the group
consisting of axitinib, pazopanib, sorafenib, sunitinib, and
everolimus.
[0501] Embodiment 32. The method of any of embodiments 24-31,
wherein the prior anti-angiogenic therapy is everolimus.
[0502] Embodiment 33. The method of any of embodiments 24-32,
wherein cabozantinib (S)-malate is administered as a tablet
comprising cabozantinib (S)-malate, microcrystalline cellulose,
anhydrous lactose, hydroxypropyl cellulose, croscarmellose sodium,
colloidal silicon dioxide magenisum stearate, and film coating
comprising hypromellose, titanium dioxide, triacetin, and iron
oxide yellow.
[0503] Embodiment 34. The method of any of embodiments 24-33,
wherein the cabozantinib (S)-malate is administered as a tablet
formulation comprising approximately:
[0504] 30-32 percent by weight of cabozantinib, (S)-malate
salt;
[0505] 38-40 percent by weight of microcrystalline cellulose;
[0506] 18-22 percent by weight of lactose;
[0507] 2-4 percent by weight of hydroxypropyl cellulose;
[0508] 4-8 percent by weight of croscarmellose sodium;
[0509] 0.2-0.6 percent by weight of colloidal silicon dioxide;
[0510] 0.5-1 percent by weight of magnesium stearate; and further
comprising:
[0511] a film coating material comprising hypromellose, titanium
dioxide, triacetin, and iron oxide yellow.
[0512] Embodiment 35. The method of any of embodiments 24-34,
wherein the cabozantinib (S)-malate is administered as a tablet
formulation comprising approximately (% w/w):
[0513] 31-32 percent by weight of cabozantinib, (S)-malate
salt;
[0514] 39-40 percent by weight of microcrystalline cellulose;
[0515] 19-20 percent by weight of lactose;
[0516] 2.5-3.5 percent by weight of hydroxypropyl cellulose;
[0517] 5.5-6.5 percent by weight of croscarmellose sodium;
[0518] 0.25-0.35 percent by weight of colloidal silicon
dioxide;
[0519] 0.7-0.8 percent by weight of magnesium stearate; and further
comprising:
[0520] 3.9-4.1 percent by weight of a film coating material
comprising hypromellose, titanium dioxide, triacetin, and iron
oxide yellow.
[0521] Embodiment 36. The method of any of embodiments 24-35,
wherein cabozantinib (S)-malate is administered as a tablet
formulation containing 20, 40, or 60 mg of cabozantinib.
[0522] Embodiment 37. The method of any of embodiments 24-36,
wherein cabozantinib (S)-malate is administered as a tablet
formulation selected from the group consisting of:
TABLE-US-00007 Theoretical Quantity (mg/unit dose) Ingredient 20-mg
Tablet* 40-mg Tablet* 60-mg Tablet* Cabozantinib (S)-malate 25.34
50.69 76.03 Microcrystalline Cellulose, PH-102 31.08 62.16 93.24
Lactose Anhydrous, 60M 15.54 31.07 46.61 Hydroxypropyl Cellulose,
EXF 2.400 4.800 7.200 Croscarmellose Sodium 4.800 9.600 14.40
Colloidal Silicon Dioxide 0.2400 0.4800 0.7200 Magnesium Stearate
(Non-Bovine) 0.6000 1.200 1.800 Opadry .RTM. Yellow (03K92254)
3.200 6.400 9.600 Total tablet weight 83.20 166.4 249.6 *Free Base
Equivalent (FBE)
[0523] Embodiment 38. The method of any of embodiments 24-37,
wherein the cabozantinib (S)-malate is administered once daily.
[0524] Embodiment 39. The method of any of embodiments 24-38,
wherein the amount of cabozantinib that is administered once daily
is 60 mg FBE.
[0525] Embodiment 40. The method of any of embodiments 24-39,
wherein the amount of cabozantinib (S)-malate is sufficient to
achieve a median time to peak plasma concentration (Tmax) of from
approximately 2 to 5 hours post-dose; and a Cmax of 200 to 500
ng/mL.
[0526] Embodiment 41. The method of any of embodiments 24-40,
wherein the overall survival of the patient are extended as
compared to the median overall survival of patients taking
everolimus; and wherein the progression-free survival of the
patient is extended over patients taking everolimus.
[0527] Embodiment 42. The method of any of embodiments 24-41,
wherein the overall survival of patients is extended as compared to
the median overall survival of patients taking everolimus; and
wherein the objective response rate is extended over patients
taking everolimus.
[0528] Embodiment 43. The method of any of embodiments 24-42,
wherein the overall survival of patients is extended as compared to
everolimus and both of progression-free survival (PFS) and
objective response rate are also extended as compared to patients
taking everolimus.
[0529] Embodiment 44. A method of treating renal cell carcinoma in
a human patient who has received prior anti-angiogenic therapy,
comprising administering to the patient an amount of cabozantinib
(S)-malate sufficient to achieve one, two, three, four, five, six,
seven, or eight effects selected from the group consisting of:
[0530] a median time to peak plasma concentration (Tmax) from 2 to
5 hours post-dose;
[0531] a Cmax of 200 to 500 ng/mL;
[0532] an AUC.sub.0-24 of 2500 to 5200 ng*h/mL;
[0533] an AUC.sub.0-t of 18,000 to 42,000 ng*h/mL;
[0534] an AUC.sub.0-.infin. of 19,000 to 45,000 ng*h/mL;
[0535] an oral volume distribution (Vz/F) of 100 to 600 L;
[0536] a terminal half-life of 90 to 135 h; and
[0537] a clearance at steady state (CL/F) of 0.7 to 3.9 L/h;
wherein:
the cabozantinib (S)-malate is administered as a tablet formulation
comprising approximately (% w/w):
[0538] 31-32 percent by weight of cabozantinib, (S)-malate
salt;
[0539] 39-40 percent by weight of microcrystalline cellulose;
[0540] 19-20 percent by weight of lactose;
[0541] 2.5-3.5 percent by weight of hydroxypropyl cellulose;
[0542] 5.5-6.5 percent by weight of croscarmellose sodium;
[0543] 0.25-0.35 percent by weight of colloidal silicon
dioxide;
[0544] 0.7-0.8 percent by weight of magnesium stearate; and further
comprising:
[0545] 3.9-4.1 percent by weight of a film coating material
comprising hypromellose, titanium dioxide, triacetin, and iron
oxide yellow.
[0546] Embodiment 45. The method of embodiment 44, wherein
cabozantinib (S)-malate is administered as a tablet formulation
containing 20, 40, or 60 mg of cabozantinib FBE.
[0547] Embodiment 46. The method of any of embodiments 44-45,
wherein cabozantinib (S)-malate is administered as a tablet
formulation selected from the group consisting of:
TABLE-US-00008 Theoretical Quantity (mg/unit dose) Ingredient 20-mg
Tablet* 40-mg Tablet* 60-mg Tablet* Cabozantinib (S)-malate 25.34
50.69 76.03 Microcrystalline Cellulose, PH-102 31.08 62.16 93.24
Lactose Anhydrous, 60M 15.54 31.07 46.61 Hydroxypropyl Cellulose,
EXF 2.400 4.800 7.200 Croscarmellose Sodium 4.800 9.600 14.40
Colloidal Silicon Dioxide 0.2400 0.4800 0.7200 Magnesium Stearate
(Non-Bovine) 0.6000 1.200 1.800 Opadry .RTM. Yellow (03K92254)
3.200 6.400 9.600 Total tablet weight 83.20 166.4 249.6 *Free Base
Equivalent (FBE)
[0548] Embodiment 47. The method of any of embodiments 44-46,
wherein the cabozantinib (S)-malate is administered in an amount
sufficient to achieve one, two, three, four, five, six, seven, or
eight effects selected from the group consisting of:
[0549] a median time to peak plasma concentration (Tmax) from 2 to
5 hours post-dose;
[0550] a Cmax of 200 to 500 ng/mL;
[0551] an AUC.sub.0-24 of 2500 to 5200 ng*h/mL;
[0552] an AUC.sub.0-t of 18,000 to 42,000 ng*h/mL;
[0553] an AUC.sub.0-.infin. of 19,000 to 45,000 ng*h/mL;
[0554] an oral volume distribution (Vz/F) of 100 to 600 L;
[0555] a terminal half-life of 90 to 135 h; and
[0556] a clearance at steady state (CL/F) of 0.7 to 3.9 L/h
[0557] Embodiment 48. The method of any of embodiments 44-47,
wherein the cabozantinib (S)-malate is administered in an amount
sufficient to achieve one, two, three, four, five, six, seven, or
eight effects selected from the group consisting of:
[0558] a median time to peak plasma concentration (Tmax) from 2.5
to 4.5 hours post-dose;
[0559] a Cmax of 250 to 450 ng/mL;
[0560] an AUC.sub.0-24 of 3000 to 4700 ng*h/mL;
[0561] an AUC.sub.0-t of 23,000 to 37,000 ng*h/mL;
[0562] an AUC.sub.0-.infin. of 24,000 to 40,000 ng*h/mL;
[0563] an oral volume distribution (Vz/F) of 150 to 550 L;
[0564] a terminal half-life of 100 to 125 h; and
[0565] a clearance at steady state (CL/F) of 1.2 to 3.2 L/h.
[0566] Embodiment 49. The method of any of embodiments 44-48,
wherein the cabozantinib (S)-malate is administered in an amount
sufficient to achieve one, two, three, four, five, six, seven, or
eight effects selected from the group consisting of:
[0567] a median time to peak plasma concentration (Tmax) from 3 to
4 hours post-dose;
[0568] a Cmax of 300 to 400 ng/mL;
[0569] an AUC.sub.0-24 of 3500 to 4200 ng*h/mL;
[0570] an AUC.sub.0-t of 28,000 to 32,000 ng*h/mL;
[0571] an AUC.sub.0-.infin. of 29,000 to 35,000 ng*h/mL;
[0572] an oral volume distribution (Vz/F) of 200 to 500 L;
[0573] a terminal half-life of 110 to 115 h; and
[0574] a clearance at steady state (CL/F) of 1.2 to 3.2
[0575] Embodiment 50. The method of any of embodiments 44-49,
wherein the cabozantinib (S)-malate is administered in an amount
sufficient to achieve one, two, three, four, five, six, seven, or
eight effects selected from the group consisting of:
[0576] a median time to peak plasma concentration (Tmax) from 3.2
to 3.8 hours post-dose;
[0577] a Cmax of 310 to 350 ng/mL;
[0578] an AUC.sub.0-24 of 3700 to 4000 ng*h/mL;
[0579] an AUC.sub.0-t of 29,000 to 30,000 ng*h/mL;
[0580] an AUC.sub.0-.infin. of 30,000 to 33,000 ng*h/mL;
[0581] an oral volume distribution (Vz/F) of 300 to 400 L;
[0582] a terminal half-life of 110 to 114 h; and
[0583] a clearance at steady state (CL/F) of 2 to 3.
[0584] Embodiment 51. The method of any of embodiments 44-50,
wherein the overall survival of the patient is extended as compared
to the median overall survival of patients taking everolimus; and
wherein the progression-free survival of the patient is extended
over patients taking everolimus.
[0585] Embodiment 52. The method of any of embodiments 44-51,
wherein the overall survival of the patient is extended as compared
to the median overall survival of patients taking everolimus; and
wherein the objective response rate is extended over patients
taking everolimus.
[0586] Embodiment 53. The method of any of embodiments 44-52,
wherein the overall survival of the patient is extended as compared
to a the median overall survival of patients taking everolimus; and
wherein progression-free survival (PFS) and objective response rate
are also extended over patients taking everolimus.
[0587] Embodiment 54. A method of treating advanced renal cell
carcinoma in patients in need of such treatment who has received
prior antiangiogenic therapy selected from the group consisting of
sunitinib therapy, pazopanib therapy, and anti-PD-1/PD-L1 immune
checkpoint inhibitor therapy, comprising administering
cabozantinib
##STR00005##
or a pharmaceutically acceptable salt thereof.
[0588] Embodiment 55. The method of embodiment 55, wherein the
cabozantinib is administered as cabozantinib (S)-malate salt.
[0589] Embodiment 56. The method of embodiment 54, wherein the
median progression free survival is at least 9.1 months when the
prior antiangiogenic therapy is sunitinib therapy only and at least
7.4 months when the prior antiangiogenic therapy is pazopanib
only.
[0590] Embodiment 57. The method of any of embodiments 54-56,
wherein the median overall survival is at least 21.4 months when
the prior antiangiogenic therapy was sunitinib only and at least
22.0 months when the prior antiangiogenic therapy was pazopanib
only.
[0591] Embodiment 58. The method of any of embodiments 54-57,
wherein the median progression free survival is at least 9.1 months
when the prior antiangiogenic therapy is sunitinib therapy only and
at least 7.4 months when the prior antiangiogenic therapy was
pazopanib only and the median overall survival is at least 21.4
months when the prior antiangiogenic therapy was sunitinib only and
at least 22.0 months when the prior antiangiogenic therapy was
pazopanib only.
[0592] Embodiment 59. A method of optimizing the treatment of a
renal carcinoma patient with a tyrosine kinase inhibitor (TKI)
comprising the step of quantifying the patient's response to one or
more dosing regimens of said TKI inhibitor with a model employing
Equation 1:
dY dt = k grow Y - ( k dmax + k dmax tol e - k tol t ) Cavg ( EC 50
+ Cavg ) Y Equation .times. .times. 1 ##EQU00002## [0593] where:
[0594] dY/dt is the change in tumor diameter per unit time [0595]
k.sub.grow is the first-order growth rate constant [0596]
k.sub.dmax is the maximum non-attenuating drug induced tumor decay
rate [0597] k.sub.dmax_tol is the maximum loss in the decay rate
due to resistance [0598] k.sub.tol is the rate constant which
governs the rate of attenuation [0599] EC.sub.50 is the
cabozantinib concentration yielding one-half of the current tumor
decay rate [0600] Cavg is the individual predicted daily average
cabozantinib concentration.
[0601] Embodiment 60. The method of embodiment 59, wherein the
target of the TKI is selected from the group consisting of VEGF
receptors, MET, and AXL.
[0602] Embodiment 61. The method of any of embodiments 59-60,
wherein the TKI inhibitor is cabozantinib.
[0603] Embodiment 62. A method of adjusting the dosing level of a
composition comprising a tyrosine kinase (TKI) inhibitor for
administration to a patient, the method comprising:
[0604] measuring plasma clearance (CL/F) and apparent volume of
distribution of the central compartment (V.sub.c/F) from a
patient;
[0605] utilizing the measured plasma clearance (CL/F) and apparent
volume of distribution of the central compartment (V.sub.c/F) to
calculate the responsiveness of the patient to the administered
composition comprising said TKI inhibitor; and [0606] comparing the
calculated responsiveness to a predetermined responsiveness to
compositions comprising said TKI inhibitor.
[0607] Embodiment 63. The method of embodiment 62, wherein the TKI
inhibitor is cabozantinb.
[0608] Embodiment 64. A method for treating renal cell carcinoma,
comprising administering as a starting dose 60 mg of cabozantinib
free base equivalent to a patient in need of such treatment,
wherein progression free survival is extended, tumor growth is
reduced, and overall response rate is extended as compared to 40 mg
or 20 mg starting doses or cabozantinib free base equivalent.
[0609] Embodiment 65. The method of claim 64, wherein cabozantinib
is administered as cabozantinib (S)-malate salt.
[0610] Embodiment 66. A method of treating renal cell carcinoma in
a human patient, wherein the method comprises administering
cabozantinib or a pharmaceutically acceptable salt thereof daily in
an amount of 60 mg of cabozantinib free base equivalent.
[0611] Embodiment 67. The method of claim 66, wherein the renal
cell carcinoma is advanced renal cell carcinoma.
[0612] Embodiment 68. The method of any of claims 66-67, wherein
the patient is an adult patient.
[0613] Embodiment 69. The method of any of embodiments 66-68,
wherein said amount is administered to the patient once daily.
[0614] Embodiment 70. The method of any of embodiments 66-69,
wherein the cabozantinib is administered as cabozantinib
(S)-malate.
[0615] Embodiment 71. The method of any of embodiments 66-70,
wherein cabozantinib (S)-malate is administered as a tablet
comprising cabozantinib (S)-malate, microcrystalline cellulose,
anhydrous lactose, hydroxypropyl cellulose, croscarmellose sodium,
colloidal silicon dioxide magenisum stearate, and film coating
comprising hypromellose, titanium dioxide, triacetin, and iron
oxide yellow.
[0616] Embodiment 72. The method of any of embodiments 66-71,
wherein the cabozantinib (S)-malate is administered as a tablet
formulation comprising approximately:
[0617] 30-32 percent by weight of cabozantinib, (S)-malate
salt;
[0618] 38-40 percent by weight of microcrystalline cellulose;
[0619] 18-22 percent by weight of lactose;
[0620] 2-4 percent by weight of hydroxypropyl cellulose;
[0621] 4-8 percent by weight of croscarmellose sodium;
[0622] 0.2-0.6 percent by weight of colloidal silicon dioxide;
[0623] 0.5-1 percent by weight of magnesium stearate; and further
comprising:
[0624] a film coating material comprising hypromellose, titanium
dioxide, triacetin, and iron oxide yellow.
[0625] Embodiment 73. The method of any of embodiments 66-72,
wherein the cabozantinib (S)-malate is administered as a tablet
formulation comprising approximately (% w/w):
[0626] 31-32 percent by weight of cabozantinib, (S)-malate
salt;
[0627] 39-40 percent by weight of microcrystalline cellulose;
[0628] 19-20 percent by weight of lactose;
[0629] 2.5-3.5 percent by weight of hydroxypropyl cellulose;
[0630] 5.5-6.5 percent by weight of croscarmellose sodium;
[0631] 0.25-0.35 percent by weight of colloidal silicon
dioxide;
[0632] 0.7-0.8 percent by weight of magnesium stearate; and further
comprising:
[0633] 3.9-4.1 percent by weight of a film coating material
comprising hypromellose, titanium dioxide, triacetin, and iron
oxide yellow.
[0634] Embodiment 74. The method of any of embodiments 66-73,
wherein the starting dose of 60 mg cabozantinib free base
equivalent can be reduced to 40 or 20 mg cabozantinib free base
equivalent to minimize adverse side effects.
[0635] Embodiment 75. The method of any of embodiments 66-74,
wherein cabozantinib (S)-malate is administered as a tablet
formulation selected from the group consisting of:
TABLE-US-00009 Theoretical Quantity (mg/unit dose) Ingredient 20-mg
Tablet* 40-mg Tablet* 60-mg Tablet* Cabozantinib (S)-malate 25.34
50.69 76.03 Microcrystalline Cellulose, PH-102 31.08 62.16 93.24
Lactose Anhydrous, 60M 15.54 31.07 46.61 Hydroxypropyl Cellulose,
EXF 2.400 4.800 7.200 Croscarmellose Sodium 4.800 9.600 14.40
Colloidal Silicon Dioxide 0.2400 0.4800 0.7200 Magnesium Stearate
(Non-Bovine) 0.6000 1.200 1.800 Opadry .RTM. Yellow (03K92254)
3.200 6.400 9.600 Total tablet weight 83.20 166.4 249.6 *Free Base
Equivalent (FBE)
[0636] Embodiment 76. The method of any of embodiments 66-75,
wherein the patient has received prior anti-angiogenic therapy.
[0637] Embodiment 77. The method of embodiment 66-76, wherein the
prior anti-angiogenic therapy is selected axitinib, pazopanib,
sorafenib, sunitinib, everolimus, temsirolimus, bevacizumab,
interleukins, interferon-.alpha., peginterferon, nivolumab,
AMP-514, and atezolizumab.
[0638] Embodiment 78. The method of embodiments 66-77, wherein the
prior anti-angiogenic therapy is everolimus therapy.
[0639] Embodiment 79. A method of treating renal cell carcinoma in
a human patient, wherein the method comprises administering
cabozantinib or a pharmaceutically acceptable salt thereof daily in
an amount of 40 mg of cabozantinib free base equivalent.
[0640] Embodiment 80. The method of embodiment 79, wherein the
renal cell carcinoma is advanced renal cell carcinoma.
[0641] Embodiment 81. The method of any of embodiments 79-80,
wherein the patient is an adult patient.
[0642] Embodiment 82. The method of any of embodiments 79-81,
wherein said amount is administered to the patient once daily.
[0643] Embodiment 83. The method of any of embodiments 79-82,
wherein the cabozantinib is administered as cabozantinib
(S)-malate.
[0644] Embodiment 84. The method of any of embodiments 79-83,
wherein cabozantinib (S)-malate is administered as a tablet
comprising cabozantinib (S)-malate, microcrystalline cellulose,
anhydrous lactose, hydroxypropyl cellulose, croscarmellose sodium,
colloidal silicon dioxide magenisum stearate, and film coating
comprising hypromellose, titanium dioxide, triacetin, and iron
oxide yellow.
[0645] Embodiment 85. The method of any of embodiments 79-84,
wherein the cabozantinib (S)-malate is administered as a tablet
formulation comprising approximately:
[0646] 30-32 percent by weight of cabozantinib, (S)-malate
salt;
[0647] 38-40 percent by weight of microcrystalline cellulose;
[0648] 18-22 percent by weight of lactose;
[0649] 2-4 percent by weight of hydroxypropyl cellulose;
[0650] 4-8 percent by weight of croscarmellose sodium;
[0651] 0.2-0.6 percent by weight of colloidal silicon dioxide;
[0652] 0.5-1 percent by weight of magnesium stearate; and further
comprising: a film coating material comprising hypromellose,
titanium dioxide, triacetin, and iron oxide yellow.
[0653] Embodiment 86. The method of any of embodiments 79-85,
wherein the cabozantinib (S)-malate is administered as a tablet
formulation comprising approximately (% w/w):
[0654] 31-32 percent by weight of cabozantinib, (S)-malate
salt;
[0655] 39-40 percent by weight of microcrystalline cellulose;
[0656] 19-20 percent by weight of lactose;
[0657] 2.5-3.5 percent by weight of hydroxypropyl cellulose;
[0658] 5.5-6.5 percent by weight of croscarmellose sodium;
[0659] 0.25-0.35 percent by weight of colloidal silicon
dioxide;
[0660] 0.7-0.8 percent by weight of magnesium stearate; and further
comprising:
[0661] 3.9-4.1 percent by weight of a film coating material
comprising hypromellose, titanium dioxide, triacetin, and iron
oxide yellow.
[0662] Embodiment 87. The method of any of embodiments 79-86,
wherein cabozantinib (S)-malate is administered as a tablet
formulation selected from the group consisting of:
TABLE-US-00010 Theoretical Quantity (mg/unit dose) Ingredient 20-mg
Tablet* 40-mg Tablet* 60-mg Tablet* Cabozantinib (S)-malate 25.34
50.69 76.03 Microcrystalline Cellulose, PH-102 31.08 62.16 93.24
Lactose Anhydrous, 60M 15.54 31.07 46.61 Hydroxypropyl Cellulose,
EXF 2.400 4.800 7.200 Croscarmellose Sodium 4.800 9.600 14.40
Colloidal Silicon Dioxide 0.2400 0.4800 0.7200 Magnesium Stearate
(Non-Bovine) 0.6000 1.200 1.800 Opadry .RTM. Yellow (03K92254)
3.200 6.400 9.600 Total tablet weight 83.20 166.4 249.6 *Free Base
Equivalent (FBE)
[0663] Embodiment 88. The method of any of embodiments 79-87,
wherein the patient has received prior anti-angiogenic therapy.
[0664] Embodiment 89. The method of embodiments 79-88, wherein the
prior anti-angiogenic therapy is selected axitinib, pazopanib,
sorafenib, sunitinib, everolimus, temsirolimus, bevacizumab,
interleukins, interferon-.alpha., peginterferon, nivolumab,
AMP-514, and atezolizumab.
[0665] Embodiment 90. The method of embodiments 79-89, wherein the
prior anti-angiogenic therapy is everolimus therapy.
[0666] Embodiment 91. A method of treating renal cell carcinoma in
a human patient, wherein the method comprises administering
cabozantinib or a pharmaceutically acceptable salt thereof daily in
an amount of 20 mg of cabozantinib free base equivalent.
[0667] Embodiment 92. The method of embodiment 91, wherein the
renal cell carcinoma is advanced renal cell carcinoma.
[0668] Embodiment 93. The method of any of embodiments 91-92,
wherein the patient is an adult patient.
[0669] Embodiment 94. The method of any of embodiments 91-93,
wherein said amount is administered to the patient once daily.
[0670] Embodiment 95. The method of any of embodiments 91-94,
wherein the cabozantinib is administered as cabozantinib
(S)-malate.
[0671] Embodiment 96. The method of any of embodiments 91-95,
wherein cabozantinib (S)-malate is administered as a tablet
comprising cabozantinib (S)-malate, microcrystalline cellulose,
anhydrous lactose, hydroxypropyl cellulose, croscarmellose sodium,
colloidal silicon dioxide magenisum stearate, and film coating
comprising hypromellose, titanium dioxide, triacetin, and iron
oxide yellow.
[0672] Embodiment 97. The method of any of embodiments 91-96,
wherein the cabozantinib (S)-malate is administered as a tablet
formulation comprising approximately:
[0673] 30-32 percent by weight of cabozantinib, (S)-malate
salt;
[0674] 38-40 percent by weight of microcrystalline cellulose;
[0675] 18-22 percent by weight of lactose;
[0676] 2-4 percent by weight of hydroxypropyl cellulose;
[0677] 4-8 percent by weight of croscarmellose sodium;
[0678] 0.2-0.6 percent by weight of colloidal silicon dioxide;
[0679] 0.5-1 percent by weight of magnesium stearate; and further
comprising:
[0680] a film coating material comprising hypromellose, titanium
dioxide, triacetin, and iron oxide yellow.
[0681] Embodiment 98. The method of any of embodiments 91-97,
wherein the cabozantinib (S)-malate is administered as a tablet
formulation comprising approximately (% w/w):
[0682] 31-32 percent by weight of cabozantinib, (S)-malate
salt;
[0683] 39-40 percent by weight of microcrystalline cellulose;
[0684] 19-20 percent by weight of lactose;
[0685] 2.5-3.5 percent by weight of hydroxypropyl cellulose;
[0686] 5.5-6.5 percent by weight of croscarmellose sodium;
[0687] 0.25-0.35 percent by weight of colloidal silicon
dioxide;
[0688] 0.7-0.8 percent by weight of magnesium stearate; and further
comprising:
[0689] 3.9-4.1 percent by weight of a film coating material
comprising hypromellose, titanium dioxide, triacetin, and iron
oxide yellow.
[0690] Embodiment 99. The method of any of embodiments 91-98,
wherein cabozantinib (S)-malate is administered as a tablet
formulation selected from the group consisting of:
TABLE-US-00011 Theoretical Quantity (mg/unit dose) Ingredient 20-mg
Tablet* 40-mg Tablet* 60-mg Tablet* Cabozantinib (S)-malate 25.34
50.69 76.03 Microcrystalline Cellulose, PH-102 31.08 62.16 93.24
Lactose Anhydrous, 60M 15.54 31.07 46.61 Hydroxypropyl Cellulose,
EXF 2.400 4.800 7.200 Croscarmellose Sodium 4.800 9.600 14.40
Colloidal Silicon Dioxide 0.2400 0.4800 0.7200 Magnesium Stearate
(Non-Bovine) 0.6000 1.200 1.800 Opadry .RTM. Yellow (03K92254)
3.200 6.400 9.600 Total tablet weight 83.20 166.4 249.6 *Free Base
Equivalent (FBE)
[0691] Embodiment 100. The method of any of embodiments 91-99,
wherein the patient has received prior anti-angiogenic therapy.
[0692] Embodiment 101. The method of embodiments 91-100, wherein
the prior anti-angiogenic therapy is selected axitinib, pazopanib,
sorafenib, sunitinib, everolimus, temsirolimus, bevacizumab,
interleukins, interferon-.alpha., peginterferon, nivolumab,
AMP-514, and atezolizumab.
[0693] 102. The method of embodiments 91-101, wherein the prior
anti-angiogenic therapy is everolimus therapy.
[0694] The invention will now be demonstrated by the following
non-limiting examples.
Example 1
Overall Survival Results from a Randomised Phase 3 Trial Comparing
Cabozantinib and Everolimus in Advanced Renal Cell Carcinoma
[0695] This study was a randomized (1:1), open-label, multicenter
study of CABOMETYX.RTM. versus everolimus conducted in patients
with advanced RCC who had received at least 1 prior anti-angiogenic
therapy. Patients had to have a Karnofsky Performance Score (KPS);
70%. Patients were stratified by the number of prior VEGFR tyrosine
kinase inhibitors and Memorial Sloan Kettering Cancer Center
(MSKCC) Risk Group.
[0696] Patients (N=658) were randomized to receive CABOMETYX.RTM.
(N=330) administered orally at 60 mg daily or everolimus (N=328)
administered orally at 10 mg daily. The majority of the patients
were male (75%), with a median age of 62 years. Sixty-nine percent
(69%) received only one prior anti-angiogenic therapy. Patient
distribution by MSKCC risk groups was 46% favorable (0 risk
factors), 42% intermediate (1 risk factor), and 13% poor (2 or 3
risk factors). Fifty-four percent (54%) of patients had 3 or more
organs with metastatic disease, including lung (63%), lymph nodes
(62%), liver (29%), and bone (22%).
[0697] The main efficacy outcome measure was progression-free
survival (PFS) assessed by a blinded independent radiology review
committee among the first 375 subjects randomized. Other efficacy
endpoints were objective response rate (ORR) and overall survival
(OS) in the Intent-to-Treat (ITT) population. Tumor assessments
were conducted every 8 weeks for the first 12 months, then every 12
weeks thereafter. Patients received treatment until disease
progression or experiencing unacceptable toxicity. Patients on both
arms who had disease progression could continue treatment at the
discretion of the investigator.
[0698] Statistically significant improvements in PFS, OS, and ORR
were demonstrated for CABOMETYX.RTM. compared to everolimus (FIG.
1.1, FIG. 1.2, and Tables 1.1 and 1.2).
TABLE-US-00012 TABLE 1.1 Progression-Free Survival in Study 1
(First 375 Randomized) CABOMETYX Everolimus Endpoint N = 187 N =
188 Median PFS (95% CI), months 7.4 (5.6, 9.1) 3.8 (3.7, 5.4) HR
(95% CI), p-value.sup.1 0.58 (0.45, 0.74), p < 0.0001
.sup.1stratified log-rank test with prior VEGFR-targeting TKI
therapy (1 vs 2 or more) and MSKCC prognostic criteria for
previously treated patients with RCC (0 vs 1 vs 2 or 3) as
stratification factors (per IVRS data)
TABLE-US-00013 TABLE 1.2 Overall Survival and Objective Response
Rate in Study 1 (ITT) CABOMETYX Everolimus Endpoint N = 330 N = 328
Median OS (95% CI), months 21.4 (18.7, NE) 16.5 (14.7, 18.8) HR
(95% CI), p-value.sup.1 0.66 (0.53, 0.83), p = 0.0003 Confirmed ORR
(partial 17% (13%, 22%) 3% (2%, 6%) responses only) (95% CI)
p-value.sup.2 p < 0.0001 .sup.1stratified log-rank test with
prior VEGFR-targeting TKI therapy (1 vs 2 or more) and MSKCC
prognostic criteria for previously treated patients with RCC (0 vs
1 vs 2 or 3) as stratification factors (per IVRS data)
.sup.2chi-squared test
[0699] Advances in the understanding of the molecular pathology of
renal cell carcinoma (RCC) have led to the development of agents
targeting the vascular endothelial growth receptor (VEGFR) and mTOR
signaling pathways. Commonly used first-line therapies in patients
with advanced RCC are the VEGFR tyrosine kinase inhibitors (TKIs)
sunitinib and pazopanib. Second-line therapies include the VEGFR
TKIs axitinib and sorafenib, the mTOR inhibitor everolimus, and the
programmed cell death receptor 1 (PD-1) checkpoint inhibitor
nivolumab. Motzer R J, Jonasch E, Agarwal N, et al. Kidney cancer,
version 3.2015. J Natl Compr Canc Netw 2015; 13: 151-9; Powles T,
Staehler M, Ljungberg B, et al. Updated EAU Guidelines for Clear
Cell Renal Cancer Patients Who Fail VEGF Targeted Therapy. Eur Urol
2016; 69: 4-6; Motzer RJ, Escudier B, McDermott D F, et al.
Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N
Engl J Med 2015; 373: 1803-13. Despite a number of available
therapies, few have shown a survival benefit, and no agent has
demonstrated an improvement in all three efficacy endpoints of
progression-free survival (PFS), objective response rate, and
overall survival in a randomized phase 3 trial compared to standard
therapy in previously-treated RCC patients.
[0700] Cabozantinib is an oral inhibitor of tyrosine kinases
including MET, VEGF receptors, and AXL. Yakes F M, Chen J, Tan J,
et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor,
simultaneously suppresses metastasis, angiogenesis, and tumor
growth. Mol Cancer Ther 2011; 10: 2298-308. Up-regulation of MET
and AXL in clear cell RCC occurs as a consequence of von
Hippel-Lindau protein dysfunction, has been implicated in tumor
progression and VEGFR-TKI resistance in preclinical studies, and
associated with a poor prognosis in RCC patients. Gibney G T, Aziz
S A, Camp R L, et al. c-Met is a prognostic marker and potential
therapeutic target in clear cell renal cell carcinoma. Ann Oncol
2013; 24: 343-9; Gustafsson A, Martuszewska D, Johansson M, et al.
Differential expression of Axl and Gas6 in renal cell carcinoma
reflecting tumor advancement and survival. Clin Cancer Res 2009;
15: 4742-9; Rankin E B, Fuh K C, Castellini L, et al. Direct
regulation of GAS6/AXL signaling by HIF promotes renal metastasis
through SRC and MET. Proc Natl Acad Sci USA 2014; 111: 13373-8;
Zhou L, Liu X D, Sun M, et al. Targeting MET and AXL overcomes
resistance to sunitinib therapy in renal cell carcinoma. Oncogene
2015 Sep. 14. doi: 10.1038/onc.2015.343; Harshman L C, Choueiri T
K. Targeting the hepatocyte growth factor/c-Met signaling pathway
in renal cell carcinoma. Cancer J 2013; 19: 316-23; Pinato D J,
Chowdhury S, Stebbing J. TAMing resistance to multi-targeted kinase
inhibitors through Axl and Met inhibition. Oncogene 2015 Oct. 5:
doi: 10.1038/onc.2015.374. The randomized phase 3 METEOR trial
compared the efficacy and safety of cabozantinib with the mTOR
inhibitor everolimus in patients with advanced RCC who progressed
after prior VEGFR-TKI therapy. Progression-free survival (PFS), the
primary endpoint, was significantly improved with cabozantinib
compared to everolimus treatment with a median PFS of 7.4 months
vs. 3.8 months (HR 0.58, 95% CI 0.45-0.75; p<0.001) as assessed
by an independent radiology review committee. Choueiri T K,
Escudier B, Powles T, et al. Cabozantinib versus Everolimus in
Advanced Renal-Cell Carcinoma. N Engl J Med 2015; 373: 1814-23. The
primary endpoint analysis was pre-specified to be conducted in the
first 375 randomized patients to provide longer follow-up in a
smaller population for the event-driven analysis. A planned interim
analysis of the secondary endpoint of overall survival in all 658
randomized patients was conducted at the time of the primary PFS
analysis and demonstrated a trend for improved survival (49%
information fraction: HR 0.67, 95% CI 0.51-0.89; p=0.005) but did
not reach the boundary for significance (p<0.0019) at this
information fraction.
[0701] We report herein the final overall survival results from the
METEOR study based on a second interim analysis. Analyses of PFS
and the objective response rate in all patients randomized are
reported as well as subgroup analyses to assess the effects of
demographics and baseline characteristics on overall survival and
progression-free survival. An update of safety data is also
provided.
[0702] Methods. 658 patients with clear cell RCC, measurable
disease, and prior therapy with .gtoreq.1 VEGFR tyrosine kinase
inhibitor (TKI) were randomized 1:1 via an interactive voice and
web response system to receive cabozantinib 60 mg daily or
everolimus 10 mg daily. Stratification factors were MSKCC risk
group and the number of prior VEGFR TKIs. The primary endpoint was
PFS as assessed by an independent radiology review committee in the
first 375 randomized patients. Secondary endpoints were overall
survival and objective response rate in all randomized patients.
The study is closed to enrolment but treatment and follow-up of
patients is on-going for long term safety evaluation. This trial is
registered at ClinicalTrials.gov, NCT01865747.
[0703] Findings. Median overall survival was 21.4 months (95%
confidence interval [CI]18.7 to not estimable) with cabozantinib
and 16.5 months (95% CI 14.7-18.8) with everolimus. The hazard
ratio (HR) for death was 0-66 (95% CI 0.53-0.83; p=0.0003).
Cabozantinib treatment also resulted in improved PFS (HR 0.51, 95%
CI 0.41-0.62; p<0.0001) and objective response rate (17% [95% CI
13-2] with cabozantinib vs. 3% [95% CI 2-6] with everolimus;
p<0.0001) per independent radiology review among all randomized
patients. The most common adverse events (all grades) were diarrhea
249 (75%), fatigue 195 (59%), and nausea 173 (52%) with
cabozantinib and fatigue 154 (48%), anemia 126 (39%), and decreased
appetite 114 (35%) with everolimus. Serious adverse events grade 3
occurred in 130 (40%) of cabozantinib-treated patients and in 129
(40%) of everolimus-treated patients.
[0704] Interpretation. Cabozantinib prolonged overall survival,
delayed disease progression, and improved the response rate
compared to standard of care everolimus in a large phase 3 trial in
previously-treated RCC patients. Patients should be monitored for
adverse events that may require dose modifications.
[0705] Study Design and Participants. METEOR is a randomized,
open-label, phase 3, international study with patients enrolled at
173 centers in 26 countries. Choueiri T K, Escudier B, Powles T, et
al. Cabozantinib versus Everolimus in Advanced Renal-Cell
Carcinoma. N Engl J Med 2015; 373: 1814-23. FIG. 1.8 depicts the
METEOR study design, and FIG. 1.10 shows the patient disposition
based on the 922 screened patients. Patients 18 years or older with
advanced or metastatic RCC and a clear cell histology were eligible
for enrolment provided they had measurable disease per RECIST
version 1.1 (See Eisenhauer E A, Therasse P, Bogaerts J, et al. New
response evaluation criteria in solid tumors: revised RECIST
guideline (version 1.1). Eur J Cancer 2009; 45: 228-47), had
received at least one prior VEGFR TKI (there was no limit to the
number of prior therapies), and had experienced disease progression
during or within 6 months of the most recent prior VEGFR-TKI
treatment and within 6 months prior to randomization. Patients were
required to have a Karnofsky Performance Status score of at least
70% and adequate organ function, based on standard laboratory tests
including hematology, serum chemistry, lipids, coagulation, thyroid
function, and urinalysis. Patients with brain metastases were
allowed provided these were stable and asymptomatic. Patients with
prior mTOR inhibitor therapy, including everolimus, were not
eligible for the study nor were patients with uncontrolled
hypertension or clinically significant cardiovascular,
gastrointestinal, wound healing, or infectious comorbidities. The
study adhered to the Good Clinical Practice guidelines and the
Declaration of Helsinki. The institutional review board or ethics
committee of the participating centers approved the study protocol.
All patients provided written informed consent.
[0706] Randomization and Masking. Patients were randomized 1:1 to
receive either cabozantinib or everolimus. Randomization was
stratified by the number of prior VEGFR-TKI therapies (1 or
.gtoreq.2) and Memorial Sloan Kettering Cancer Center (MSKCC) risk
group (favorable, intermediate, or poor) for previously-treated
patients (Table 1.3). Motzer R J, Bacik J, Schwartz L H, et al.
Prognostic factors for survival in previously treated patients with
metastatic renal cell carcinoma. J Clin Oncol 2004; 22: 454-63.
TABLE-US-00014 TABLE 1.3 Memorial Sloan-Kettering Cancer Center
(MSKCC) Prognostic Criteria for Previously Treated Patients with
Renal Cell Carcinoma Number of Risk Factors* Expected Outcome 0
Favorable 1 Intermediate 2 or 3 Poor See Motzer RJ, Bacik J,
Schwartz LH, et al. Prognostic factors for survival in previously
treated patients with metastatic renal cell carcinoma. J Clin Oncol
2004; 22: 454-63. *The three risk factors are: Karnofsky
performance status score <80%; Hemoglobin <13 g/dL for males
or <11.5 g/dL for females; Corrected calcium > upper limit of
normal.
[0707] The study employed stratified permuted blocks as the
randomization schema. Study treatment was assigned centrally using
an interactive voice and web response system. Study personnel did
not have access to the master list of blocks or block sizes.
Patients and investigators were not masked to study treatment to
allow appropriate management of adverse events. Aggregate summaries
of efficacy data by treatment arm were not performed until the time
of the primary PFS analysis.
[0708] Procedures. Cabozantinib was taken orally once daily at 60
mg, and everolimus was taken orally once daily at 10 mg. Treatment
modifications, including interruptions and dose reductions, were
allowed to manage adverse events. Cabozantinib could be
dose-reduced to 40 mg and then 20 mg, and everolimus could be
dose-reduced to 5 mg and then 2.5 mg. Patients were allowed to
continue study treatment beyond radiographic progression at the
discretion of the investigator. On-study crossover between
treatment groups was not permitted. Safety evaluations, including
physical examination, vital signs, and laboratory assessments, were
conducted every 2 weeks for the first 8 weeks and then every 4
weeks thereafter. ECG assessments were performed every 4 weeks for
the first 8 weeks and then every 12 weeks. A safety follow-up visit
was scheduled 30 days after treatment discontinuation. Adverse
events were assessed by investigators and graded according to CTCAE
version 4.0. National Cancer Institute. Common Terminology Criteria
for Adverse Events (CTCAE) v.4. Posted at
evs.nci.nih.gov/ftp1/CTCAE/About.html (accessed Jan. 28, 2015; last
visited Apr. 14, 2017).
[0709] Radiographic assessments by CT or MRI were conducted at
screening and every 8 weeks for the first 12 months and then every
12 weeks thereafter. Tumor response and progression were assessed
according to Response Evaluation Criteria in Solid Tumors (RECIST)
version 1.1 (Eisenhauer E A, Therasse P, Bogaerts J, et al. New
response evaluation criteria in solid tumors: revised RECIST
guideline (version 1.1). Eur J Cancer 2009; 45: 228-47) by a masked
centralized independent radiology review committee. Patients were
followed for overall survival every eight weeks.
[0710] Tumor tissue (archival or recently biopsied) was obtained at
enrollment when available for immunohistochemistry (IHC) analysis
of MET. Formalin-fixed paraffin embedded (FFPE) tumor blocks or
freshly cut FFPE slides were analyzed by LabCorp using the SP44
antibody (Spring Biosciences, Pleasanton, Calif.). MET expression
was defined as high versus low, based on a cutoff of .gtoreq.50% of
tumor tissue stained with an intensity of 2+ or 3+ by IHC,
according to published procedures. Spigel D R, Ervin T J, Ramlau R
A, et al. Randomized phase II trial of Onartuzumab in combination
with erlotinib in patients with advanced non-small-cell lung
cancer. J Clin Oncol 2013; 31: 4105-14; Santoro A, Rimassa L,
Borbath I, et al. Tivantinib for second-line treatment of advanced
hepatocellular carcinoma: a randomized, placebo-controlled phase 2
study. Lancet Oncol 2013; 14: 55-63.
[0711] Outcomes. The primary endpoint was PFS by independent
radiology review in the first 375 randomized patients. PFS was
defined as the time from randomization to radiographic progression
per RECIST version 1.1 or death. Secondary endpoint analyses of
overall survival and objective response rate (as determined by
independent radiology review) were conducted in all randomized
patients. Overall survival was defined as the time from
randomization to death from any cause, and objective response rate
was defined as the proportion of patients experiencing a confirmed
complete or partial response per RECIST 1.1. Safety and
tolerability were also assessed.
[0712] Statistical analysis. The study was designed to provide
adequate power for both PFS and overall survival. The statistical
design of the study is depicted in FIG. 1.9. For the primary
endpoint of PFS, the event-driven analysis (at the 2-sided 5% alpha
level) required 259 PFS events. The secondary endpoints of overall
survival (at the 2-sided 4% alpha level) and objective response
rate (at the 2-sided 1% alpha level) were to be tested among all
randomized patients (the intention-to-treat (ITT) population) only
if the primary PFS endpoint achieved statistical significance. For
overall survival, assuming a single interim analysis at the time of
the primary endpoint analysis and a subsequent final analysis, 408
deaths were required to provide 80% power to detect a hypothesized
HR of 0.75 corresponding to an improvement in median survival from
15 months (Motzer R J, Escudier B, Oudard S, et al. Phase 3 trial
of everolimus for metastatic renal cell carcinoma: final results
and analysis of prognostic factors. Cancer 2010; 116: 4256-65) to
20 months. With a planned average accrual rate of 32 patients per
month and using a 1:1 treatment allocation ratio, a total of 650
patients were required to observe 408 deaths within the planned
study duration of 36 months. As the total sample size of 650
required to evaluate overall survival was much larger than needed
to assess the primary endpoint of PFS, there was the possibility
that patients with earlier progression intervals would be
overrepresented (and those with longer progression intervals
underrepresented) among the planned 259 PFS events. To reduce this
potential, the primary analysis of PFS was pre-specified to occur
when the required 259 events were observed in the first 375
randomized patients, the size the study would have been without the
overall survival endpoint. Supportive analyses of PFS among all
randomized patients were also planned.
[0713] The planned interim analysis of overall survival (conducted
at the time of the primary PFS analysis with a data cutoff of May
22, 2015; minimum follow-up of 6 months) demonstrated a trend for
longer survival that at that time did not meet the boundary for
significance (49% information fraction: p<0.0019) defined by the
Lan-DeMets O'Brien-Fleming alpha spending function. The results of
the planned interim analysis of overall survival were made public
in July 2015 and were published in September 2015. Choueiri T K,
Escudier B, Powles T, et al. Cabozantinib versus Everolimus in
Advanced Renal-Cell Carcinoma. N Engl J Med 2015; 373: 1814-23. The
decision to conduct an unplanned second interim analysis was made
by the sponsor in consultation with regulatory agencies. As a
result, the analysis plan was revised in October 2015 to include an
unplanned second interim analysis of overall survival with a
prospectively-defined cutoff date of Dec. 31, 2015, to provide a
minimum of 13 months of follow-up from the last patient
enrolled.
[0714] Hypothesis testing of duration of overall survival and PFS
was performed using the stratified log-rank test with the same
stratification factors as for randomization. Median duration of PFS
and overall survival, corresponding 95% confidence intervals, and
landmark proportions were estimated by the Kaplan-Meier method.
Hazard ratios were estimated with a Cox regression model.
Hypothesis testing for objective response rate was performed using
the 2-sided chi-square test, and confidence intervals for
proportions were calculated using exact methods. All subgroup
analyses were pre-specified except for the subgroups that had
received prior sunitinib and prior pazopanib as their only prior
VEGFR TKI. P-values and confidence intervals for subgroup analyses
are considered descriptive. Safety analyses were limited to
patients who received any amount of study treatment.
[0715] All analyses were conducted using SAS.RTM. software Version
9.1 or higher (SAS Institute, Inc., Cary, N.C.).
[0716] This trial is registered at ClinicalTrials.gov,
NCTO1865747.
Results
[0717] Between Aug. 8, 2013, and Nov. 24, 2014, 658 patients were
randomized to receive cabozantinib (n=330) or everolimus (n=328)
(FIG. 1.3). As of Dec. 31, 2015, the cutoff for the second interim
analysis of overall survival, 74 of 330 patients (22%) in the
cabozantinib group and 25 of 328 patients (8%) in the everolimus
group remained on study treatment. Demographics and baseline
characteristics were typical of patients with advanced RCC and
balanced between treatment groups (Table 1.4). Choueiri T K,
Escudier B, Powles T, et al. Cabozantinib versus Everolimus in
Advanced Renal-Cell Carcinoma. N Engl J Med 2015; 373: 1814-23.
TABLE-US-00015 TABLE 1.4 Demographics and Baseline Characteristics
Cabozantinib Everolimus (N = 330) (N = 328) Age, median (range)
years 63 (32-86) 62 (31-84) Sex, n (%) Male 253 (77) 241 (73)
Female 77 (23) 86 (26) Not reported 0 1 (<1) Geographic region,
n (%) Europe 167 (51) 153 (47) North America 118 (36) 122 (37)
Asia-Pacific 39 (12) 47 (14) Latin America 6 (2) 6 (2) Race, n (%)
White 269 (82) 263 (80) Asian 21 (6) 26 (8) Black 6 (2) 3 (<1)
Other 19 (6) 13 (4) Not reported 15 (5) 22 (7) Missing data 0 1
(<1) ECOG performance-status score, n (%) 0 226 (68) 217 (66) 1
104 (32) 111 (34) MSKCC prognostic risk category, n (%)* Favorable
150 (45) 150 (46) Intermediate 139 (42) 135 (41) Poor 41 (12) 43
(13) Metastatic site, n (%) Lung 204 (62) 212 (65) Liver 88 (27)
103 (31) Bone 77 (23) 65 (20) Lymph node 206 (62) 199 (61) Brain 2
(<1) 1 (<1) Other 23 (7) 21 (6) Sum of lesions diameters, 65
(0-291) 65 (0-258) median (range), mm Prior VEGFR tyrosine kinase
inhibitors, n (%) 1 235 (71) 229 (70) .gtoreq.2 95 (29) 99 (30)
Previous systemic therapy, n (%) Sunitinib 210 (64) 205 (62)
Pazopanib 144 (44) 136 (41) Axitinib 52 (16) 55 (17) Sorafenib 21
(6) 31 (9) Bevacizumab 5 (2) 11 (3) Interleukin-2 20 (6) 29 (9)
Interferon alfa 19 (6) 24 (7) Nivolumab 17 (5) 14 (4) Radiotherapy,
n (%) 110 (33) 108 (33) Nephrectomy, n (%) 282 (85) 279 (85)
[0718] A total of 464 patients (71%) had received only one prior
VEGFR TK1, and the most common prior VEGFR TKIs were sunitinib (415
[63%]) and pazopanib (280 [43%]). Thirty-two (5%) had received
prior immunotherapy with a PD-1 checkpoint inhibitor, primarily
nivolumab. The most frequent reason for treatment discontinuation
in both groups was disease progression. The median duration of
follow-up for overall survival and safety was 18.7 months (IQR
16.1-21.1) in the cabozantinib group and 18.8 months (IQR
16.0-21.2) in the everolimus group. The data cutoff for PFS and
objective response rate analyses among all enrolled patients was
the same as for the primary PFS endpoint analysis (May 22, 2015)
with a median duration of follow-up of 11.4 months (IQR 8.8-13.7)
in the cabozantinib group and 11.5 months (IQR 8.6-13.9) in the
everolimus group. Choueiri T K, Escudier B, Powles T, et al.
Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma. N
Engl J Med 2015; 373: 1814-23.
[0719] The second interim analysis of overall survival included 320
deaths, representing 78% of the 408 deaths planned for the
pre-specified final analysis of overall survival. There were 140
deaths out of 330 patients (42%) in the cabozantinib group and 180
deaths out of 328 patients (55%) in the everolimus group. Survival
status as of the cutoff date was determined for the majority (98%)
of the 658 randomized patients.
[0720] Treatment with cabozantinib significantly improved overall
survival compared to everolimus in the second interim analysis.
FIG. 1.4 is a Kaplan-Meier plot of overall survival through Dec.
31, 2015. All 658 randomized patients were included in the
analysis. The number of patients censored is summarized by
interval. CI indicates confidence interval, and NE means not
estimable. The median overall survival was 21.4 months (95% CI
18.7-not estimable [NE]) in the cabozantinib group compared with
16.5 months (95% CI 14.7-18.8) in the everolimus group. The hazard
ratio was 0.66 (95% CI 0.53-0.83; p=0.0003), which met the
criterion for significance (p<0.0163) from the pre-specified
alpha spending function.
[0721] Kaplan-Meier landmark estimates up to 24 months showed that
at each time point the proportion of patients estimated to be alive
was greater among patients in the cabozantinib group compared to
patients in the everolimus group (Table 1.5).
TABLE-US-00016 TABLE 1.5 Kaplan-Meier Estimates of Percent of
Patients Alive at Selected Landmarks Estimate of % of Patients
Alive with 95% CI Cabozantinib Everolimus Landmark N = 330 N = 328
6 Months 91% (87%, 93%) 81% (76%, 85%) 12 Months 73% (68%, 79%) 63%
(58%, 78%) 18 Months 58% (53%, 64%) 47% (41%, 52%) 24 Months 48%
(39%, 55%) 31% (23%, 39%)
[0722] FIG. 1.5A and FIG. 1.5B depict Forest plots of overall
survival and progression-free survival. All 658 randomized patients
were included in the analyses of overall survival and
progression-free survival, which were conducted with a data cutoff
of Dec. 31, 2015, and May 22, 2015, respectively. Disease
progression was assessed by an independent radiology review
committee. Hazard ratios are estimates from the Cox
Proportional-Hazards model and are un-stratified with the exception
of those for the overall population, which use the stratification
factors for randomization. The PFS analysis included 48, 138, and
144 patients with high, low, and unknown MET status, respectively
in the cabozantinib group and 48, 151, and 129 patients in the
everolimus group, respectively, which was the known MET status of
patients as of the May 22, 2015 data cutoff. CI, confidence
interval; HR, hazard ratio; IMDC, International Metastatic Renal
Cell Carcinoma Database Consortium; MSKCC, Memorial Sloan Kettering
Cancer Center; PD-1, programmed cell death protein-1; PD-L1,
programmed cell death ligand-1; SoD, sum of lesion diameters; TKI,
tyrosine kinase inhibitor; VEGFR, vascular endothelial growth
factor receptor.
[0723] At 12 months estimates of survival were 73% (95% CI 68%,
78%) in the cabozantinib group compared with 63% (58%, 78%) in the
everolimus group. At 18 months the estimates were 58% (53%, 64%) in
the cabozantinib group compared with 47% (41%, 52%) in the
everolimus group.
[0724] Subgroup analyses of overall survival were consistent with
the results for the overall population with a hazard ratio <1
for all subgroups analyzed (FIG. 1.3). Subgroups defined by MSKCC
risk groups of favorable, intermediate, and poor had similar hazard
ratios for overall survival ranging from 0.65 to 0.67. These
results are depicted in FIG. 1.11. Patients who received sunitinib
or pazopanib as their only prior VEGFR-TKI therapy also had a
similar overall survival benefit with cabozantinib treatment
(hazard ratio of 0.66 for both subgroups). These results are
depicted in FIG. 1.12. A marked benefit was observed in patients
with bone metastases; the hazard ratio was 0.54 (95% CI 0.34-0.84)
for patients with bone metastases and 0-45 (95% CI 0.28-0.72) for
those patients with bone metastases who also had visceral
metastases. These results are depicted in FIG. 1.13.
[0725] FIG. 1.14 depicts patient disposition (ITT Population).
FKSI, FACT Kidney Symptom Index; EQ-5D, EuroQoL 5D Utility Score.
Baseline FKSI-19 (EQ-5D-5L) data were available for 324 (323)
patients in the cabozantinib arm and 313 (314) in the everolimus
arm, of whom 319 (317) and 303 (304), respectively, had at least
one post-baseline assessment. (a) Five patients randomized to the
everolimus arm did not receive study treatment. In addition, one
patient randomized to receive everolimus received cabozantinib as
study treatment. (b) Includes withdrawals, protocol deviations,
lack of efficacy, investigator decision.
[0726] FIG. 1.15A and FIG. 1.5B plot absolute FKSI ccores over time
(ITT Population). A. FKSI-19 Total. B. 9-item FKSI-DRS. DRS,
disease-related symptoms; FKSI, FACT Kidney Symptom Index; PD,
progressive disease; rPD, radiographic progressive disease; TRT,
treatment; QoL, quality of life; W, week. Higher scores indicate
improved QoL status. Peri Last Dose is the closest QoL assessment 2
wks before to 4 wks after last dose. Peri rPD per Inv is the
closest QoL assessment 2 wks before to 4 wks after first date of PD
per investigator.
[0727] FIG. 1.16 depicts the effect of baseline FKSI-DRS on OS (ITT
Population). CI, confidence interval; DRS, disease-related
symptoms; FKSI, FACT Kidney Symptom Index; HR, hazard ratio; mo,
month; OS, overall survival; QoL, quality of life.
[0728] Kaplan-Meier plots of overall survival for patients with
high and low tumor MET status are shown in the FIG. 1.6A and FIG.
1.6B. For patients with high MET tumor expression, the hazard ratio
was 0.55 (95% CI 0.31 to 0.99) and median overall survival was 22.0
months (95% CI 15.4-NE) with cabozantinib and 15.2 months (95% CI
8.7-NE) with everolimus. For patients with low MET tumor
expression, the hazard ratio was 0.72 (95% CI, 0.52-1.00), and
median overall survival was 20.8 months (95% CI 18.1-NE) with
cabozantinib and 18.4 months (95% C1 15.9-19.6) with
everolimus.
[0729] The proportions of patients continuing study treatment for
at least two weeks after radiographic progression were similar
between groups (74 [38%] with cabozantinib and 71 [31%] with
everolimus). Also, similar proportions of patients in the
everolimus group and the cabozantinib group were reported to have
received subsequent systemic anticancer therapy following study
treatment discontinuation (181 [55%] vs. 165 [50%) (Table 1.6).
TABLE-US-00017 TABLE 1.6 Subsequent Anticancer Therapies
Cabozantinib Everolimus N = 330 N = 328 n (%) n (%) Systemic
therapy 165 (50) 181 (55) VEGFR-TKI Therapies 79 (24) 155 (47)
Axitinib 57 (17) 90 (27) Cabozantinib.sup.a 0 7 (2) Pazopanib 5 (2)
22 (7) Sorafenib 9 (3) 31 (9) Sunitinib 17 (5) 33 (10) Other
Selected Systemic Therapies Everolimus.sup.a 96 (29) 15 (5)
Temsirolimus 6 (2) 4 (1) Bevacizumab 8 (2) 11 (3) Interleukins
(Interleukin 2) 0 4 (1) Interferon-.alpha./Peginterferon 5 (2) 7
(2) PD-1/PD-L1 targeting agents.sup.b 15 (5) 19 (6) Chemotherapy 11
(3) 13 (4) External beam radiotherapy 61 (18) 77 (23) Surgery
(tumor lesions) 13 (4) 9 (3) Note: patients may have received more
than one type of anticancer therapy. .sup.aRefers to commercial
use. .sup.b14 patients received nivolumab and one received
pembrolizumab. In the everolimus arm, 16 patients received
nivolumab, two received AMP-514, and one received MPDL3280A
(atezolizumab). PD-1, programmed cell death protein-1; PD-L1,
programmed cell death ligand-1; TKI, tyrosine kinase inhibitor;
VEGFR, vascular endothelial growth factor receptor
[0730] Patients in the everolimus group more frequently received
subsequent VEGFR-TKI therapy (155 [47%] vs. 79 [24%]), most
frequently axitinib (90 [27%] vs. 57 [17%]), whereas patients in
the cabozantinib group more frequently received everolimus (96
[29%] in the cabozantinib group vs. 15 [5%] in the everolimus
group). The proportion of patients receiving subsequent therapies
targeting PD-1/PD-L1 was low (about 5%) and balanced in both
treatment groups.
[0731] FIG. 1.7 is a Kaplan-Meier plot of progression-free survival
as of May 22, 2015. Disease progression was assessed by an
independent radiology review committee in all 658 randomized
patients. The number of patients censored is summarized by
interval. CI, confidence interval; No, number, PFS,
progression-free survival. The analysis of PFS per independent
radiology review conducted in all 658 randomized patients
demonstrated improved PFS with cabozantinib: the hazard ratio was
0.51 (95% CI, 0.41-62; p<0.0001). Kaplan-Meier estimates for
median duration of PFS were 7.4 months (95% CI 6.6-9.1) in the
cabozantinib group versus 3.9 months (95% CI 3.7-5.1) in the
everolimus group. Results for PFS per investigator assessment (HR
0.54, 95% CI 0.45-0.66) were similar to those determined by the
independent radiology review committee (Table 1.7).
TABLE-US-00018 TABLE 1.7 Progression-Free Survival as of the May
22, 2015 Cutoff Date IRC Investigator Cabozantinib Everolimus
Cabozantinib Everolimus N = 330 N = 328 N = 330 N = 328 Event, n
(%) 180 (55) 214 (66) 196 (59) 233 (71) Median 7.4 (6.6-9.1) 3.9
(3.7-5.1) 7.4 (7.3-7.8) 5.1 (3.9-5.5) duration of progression- free
survival (95% confidence interval) (months) Stratified <0.0001
<0.0001 p-value Hazard ratio 0.52 (0.42-0.64) 0.54 (0.45-0.66)
(95% confidence interval) Median is based on Kaplan-Meier survival
estimates. Stratification factors were those used for
randomization. The hazard ratio was estimated using the Cox
proportional hazard model adjusted for stratification factors.
Hazard ratio <1 indicates progression-free survival (PFS) in
favor of cabozantinib. IRC, independent radiology review
committee
[0732] Subgroup analyses of PFS per independent radiology review to
assess the effects of demographics and baseline characteristics
were consistent with the results for the overall population with
all hazard ratios <1 (FIG. 1.5 A and FIG. 1.5B), demonstrating
an improvement in PFS with cabozantinib treatment for all subgroups
analyzed.
[0733] The objective response rate per independent radiology review
in all 658 randomized patients was 17% (95% CI 13-22) (57 partial
responses) for the cabozantinib group and 3% (95% CI 2-6) (11
partial responses) for the everolimus group (p<0.0001) (Table
1.8).
TABLE-US-00019 TABLE 1.8 Tumor Response as of the May 22, 2015
Cutoff Date Cabozantinib Everolimus N = 330 N = 328 IRC
Investigator IRC Investigator Objective 17 (13-22).sup.b 24
(19-29).sup.b 3 (2-6) 4 (2-7) response rate (95% confidence
interval).sup.a Best overall response, n (%) Confirmed 0 0 0 0
complete response Confirmed 57 (17) 78 (24) 11 (3) 14 (4) partial
response Stable disease 216 (65) 209 (63) 203 (62) 205 (63)
Progressive 41 (12) 29 (9) 88 (27) 87 (27) disease Not evaluable 16
(5) 14 (4) 26 (8) 22 (7) or missing.sup.c .sup.aThe proportion of
patients achieving an overall response of confirmed complete
response or partial response per RECIST version 1.1. .sup.bThe
p-value from Cochran-Mantel-Haenszel test with stratification
factors used for randomization was < 0.0001 for both IRC and
investigator-determined response compared to everolimus. .sup.cNo
qualifying post-baseline assessment for overall response. IRC,
independent radiology review committee
[0734] A best response of stable disease was observed for 216
patients (65%) in the cabozantinib group and 203 (62%) in the
everolimus group. The incidence of progressive disease as best
response was low with cabozantinib (41/330 [12%]) compared to
everolimus (88/328 [27%]). Results for tumor response per
investigator assessment were similar to those determined by the
independent radiology review committee (Table 1.8); the objective
response rate per investigator was 24% (95% CI 19-29) and 4% (95%
CI 2-7) for patients in the cabozantinib and everolimus groups,
respectively.
[0735] As of the Dec. 31, 2015, cutoff for the overall survival
analysis, the median duration of exposure was 8.3 months (IQR
4.2-14.6) in cabozantinib-treated patients (n=331) and 4.2 months
(IQR 1.9-8.6) in the everolimus-treated patients (n322). Dose
reductions occurred for 206 patients (62%) treated with
cabozantinib and 80 patients (25%) treated with everolimus. The
median daily dose was 43 mg cabozantinib (IQR 36-56) and 9 mg
everolimus (IQR 7-10). Treatment discontinuation due to an adverse
event not related to disease progression was 12% (41/330) in the
cabozantinib group and 10% (34/328) in the everolimus group.
[0736] The overall incidence of adverse events regardless of
causality was 100% (331/331) for the cabozantinib group and >99%
(321/322) for the everolimus group. Grade 3 or 4 adverse events
were experienced by 235 (71%) and 193 (60%) of cabozantinib- and
everolimus-treated patients, respectively (Table 1.9).
TABLE-US-00020 TABLE 1.9 Adverse Events Cabozantinib Everolimus (N
= 331) n (%) (N = 322) n (%) Grade Grade Grade Grade Grade Grade
Event 1-2 3 4 1-2 3 4 Any AE 70 (21) 210 (63) 25 (8) 103 (32) 167
(52) 26 (8) Diarrhea 206 (62) 43 (13) 0 85 (26) 7 (2) 0 Fatigue 159
(48) 36 (11) 0 130 (40) 24 (8) 0 Nausea 158 (48) 15 (5) 0 92 (29) 1
(<1) 0 Decreased appetite 146 (44) 10 (3) 0 111 (35) 3 (<1) 0
Palmar-plantar 115 (35) 27 (8) 0 16 (5) 3 (<1) 0
erythrodysaesthesia syndrome Vomiting 106 (32) 7 (2) 0 44 (14) 3
(<1) 0 Weight decreased 105 (32) 9 (3) 0 42 (13) 0 0
Constipation 89 (27) 1 (<1) 0 64 (20) 1 (<1) 0 Dysgeusia 80
(24) 0 0 30 (9) 0 0 Hypothyroidism 76 (23) 0 0 1 (<1) 1 (<1)
0 Hypertension 73 (22) 49 (15) 0 14 (4) 12 (4) 0 Dysphonia 68 (21)
2 (<1) 0 16 (5) 0 0 Cough 67 (20) 1 (<1) 0 107 (33) 3 (<1)
0 Stomatitis 65 (20) 8 (2) 0 71 (22) 7 (2) 0 Mucosal inflammation
60 (18) 5 (2) 0 64 (20) 10 (3) 1 (<1) Dyspnoea 56 (17) 10 (3) 0
82 (26) 11 (3) 3 (<1) Aspartate aminotransferase 55 (17) 5 (2) 0
19 (6) 1 (<1) 0 increased Back pain 54 (16) 8 (2) 0 41 (13) 7
(2) 0 Rash 52 (16) 2 (<1) 0 92 (29) 2 (<1) 0 Asthenia 49 (15)
15 (5) 0 46 (14) 8 (3) 0 Abdominal pain 48 (15) 12 (4) 0 27 (8) 5
(2) 0 Alanine aminotransferase 47 (14) 7 (2) 1 (<1) 20 (6) 1
(<1) 0 increased Pain in extremity 46 (14) 5 (2) 0 31 (10) 1
(<1) 0 Muscle spasms 45 (14) 0 0 17 (5) 0 0 Arthralgia 43 (13) 1
(<1) 0 46 (14) 4 (1) 0 Headache 43 (13) 1 (<1) 0 42 (13) 1
(<1) 0 Anemia 42 (13) 19 (6) 0 73 (23) 53 (17) 0 Dizziness 41
(12) 1 (<1) 0 21 (7) 0 0 Dyspepsia 40 (12) 1 (<1) 0 15 (5) 0
0 Edema peripheral 39 (12) 0 0 70 (22) 6 (2) 0 Hypomagnesaemia 38
(12) 6 (2) 10 (3) 5 (2) 0 0 Dry skin 37 (11) 0 0 35 (11) 0 0
Proteinuria 37 (11) 8 (2) 0 28 (9) 2 (<1) 0 Flatulence 33 (10) 0
0 7 (2) 0 0 Insomnia 32 (10) 0 0 33 (10) 1 (<1) 0 Pyrexia 31 (9)
3 (<1) 0 57 (18) 2 (<1) 0 Pruritus 27 (8) 0 0 48 (15) 1
(<1) 0 Blood creatinine increased 17 (5) 1 (<1) 0 39 (12) 0 0
Hypertriglyceridemia 17 (5) 4 (1) 0 31 (10) 7 (2) 3 (<1)
Hyperglycemia 15 (5) 2 (<1) 1 (<1) 46 (14) 16 (5) 0 Epistaxis
14 (4) 0 0 46 (14) 0 0
[0737] The most common grade 3 or 4 adverse events with
cabozantinib were hypertension (49 [15%]), diarrhea (43 [13%]), and
fatigue (36 [11%]) and with everolimus were anemia (53 [17%]),
fatigue (24 [7%]), and hyperglycemia (16 [5%]). Among these, no
grade 4 adverse events were reported in either treatment group.
[0738] Serious adverse events .gtoreq.grade 3 occurred in 130 (40%)
of cabozantinib-treated patients and in 129 (40%) of
everolimus-treated patients. Grade 5 adverse events regardless of
causality were reported for 26 patients (7.9%) in the cabozantinib
group and 25 (7.8%) in the everolimus group; the majority of these
were related to disease progression. One grade 5 adverse event was
assessed as treatment-related in the cabozantinib group (death; not
otherwise specified) and two in the everolimus group (aspergillus
infection, pneumonia aspiration).
Discussion
[0739] This randomized phase 3 study demonstrated a highly
significant overall survival benefit for cabozantinib treatment
compared with everolimus in patients with previously-treated
advanced RCC. The median overall survival was 21.4 months with
cabozantinib as compared with 16.5 months with everolimus (HR 0.66;
p=0.0003). PFS was significantly improved, and a higher objective
response rate was observed for cabozantinib as compared with
everolimus. The median PFS was 7.4 months in the cabozantinib group
versus 3,9 months in the everolimus group in all randomized
patients, which is consistent with the results previously reported
for the first 375 randomized patients (the primary endpoint of the
study). Choueiri T K, Escudier B, Powles T, et al. Cabozantinib
versus Everolimus in Advanced Renal-Cell Carcinoma. N Engi J Med
2015; 373: 1814-23. Objective tumor responses per independent
radiology review committee were observed for 17% of patients who
received cabozantinib and 3% of patients who received everolimus,
which is also consistent with the previously reported results for
the first 375 randomized patients.
[0740] The updated safety profile of cabozantinib was similar to
that previously reported at the earlier data cutoff for this study.
The most common adverse events were typical of those observed with
other VEGFR TKIs in RCC patients and included diarrhea, fatigue,
nausea, decreased appetite, palmar-plantar erythrodysaesthesia
syndrome, and hypertension. Eisen T, Sternberg C N, Robert C, et
al. Targeted therapies for renal cell carcinoma: review of adverse
event management strategies. J Natl Cancer Inst 2012; 104: 93-113.
The adverse event profile for everolimus was similar to that
observed in other clinical studies. Motzer R J, Escudier B, Oudard
S, et al. Phase 3 trial of everolimus for metastatic renal cell
carcinoma: final results and analysis of prognostic factors. Cancer
2010; 116: 4256-65. Adverse events were managed with dose
modifications and supportive care in both treatment groups.
Although the frequency of dose reductions was higher in the
cabozantinib-treated group, the rate of treatment discontinuations
due to adverse events were similar in both groups (12% cabozantinib
group vs.10% everolimus group), indicating that dose modifications
were effective in minimizing or preventing treatment-associated
discontinuations.
[0741] Both the overall survival and PFS benefits were consistently
observed across all subgroups analyzed including those defined by
the pre-specified stratification factors (MSKCC risk group and
number of prior VEGFR TKIs), International Metastatic Renal Cell
Carcinoma Database Consortium (IMDC) risk group (Ko J J, Xie W,
Kroeger N, et al. The International Metastatic Renal Cell Carcinoma
Database Consortium model as a prognostic tool in patients with
metastatic renal cell carcinoma previously treated with first-line
targeted therapy: a population-based study. Lancet Oncol 2015; 16:
293-300), duration of prior VEGFR-TKI therapy, and prior treatment
with agents targeting PD-1/PD-L1, location and extent of tumor
metastases. The most common prior therapies were sunitinib and
pazopanib, consistent with standard clinical practice. Motzer R J,
Jonasch E, Agarwal N, et al. Kidney cancer, version 3.2015. J Natl
Compr Cane Netw 2015; 13: 151-9. Patients who received either
sunitinib or pazopanib as their only prior VEGFR TKI had an overall
survival benefit with cabozantinib treatment that was similar to
the overall population. The marked overall survival benefit in
patients with bone metastases, which are associated with a poor
prognosis (McKay R R, Kroeger N, Xie W, et al. Impact of bone and
liver metastases on patients with renal cell carcinoma treated with
targeted therapy. Eur Urol 2014; 65: 577-84), is consistent with
reported effects of cabozantinib on bone metastases in both
clinical and preclinical studies (Choueiri T K, Pal S K, McDermott
D F. et al. A phase I study of cabozantinib (XL 184) in patients
with renal cell cancer. Ann Oncol 2014; 25: 1603-8; Graham T I, Box
G, Tunariu N, et al. Preclinical evaluation of imaging biomarkers
for prostate cancer bone metastasis and response to cabozantinib. J
Natl Cancer Inst 2014; 106: dju033), and warrants further
investigation into the mechanisms underlying the activity of
cabozantinib in bone.
[0742] The proportions of patients continuing study treatment for
at least two weeks after radiographic progression were similar
between groups. Subsequent anticancer therapy was also balanced
between treatment groups after study treatment discontinuation.
Therefore, these factors are deemed unlikely to have biased the
results overall survival towards one treatment group. In addition,
treatment crossover was not allowed after determination of the
primary endpoint of PFS enabling robust assessment of overall
survival.
[0743] Although the study used an open-label design, bias was
minimized for the primary endpoint of PFS and secondary endpoint of
objective response rate by evaluation of radiographic assessments
by a masked central independent radiology review committee. In
addition, radiographic assessments were continued beyond
investigator-determined progression in order to reduce missing data
arising from discordance on the date of progression between the
investigator and the independent radiology review committee. An
advantage of open-label design is appropriate management of adverse
effects in both study groups.
[0744] High MET expression in patients with advanced RCC has been
associated with both a poor prognosis and prior exposure to VEGFR
TKIs, and in preclinical models is associated with resistance to
VEGFR TKI treatment. Gibney G T, Aziz S A, Camp R L, et al. c-Met
is a prognostic marker and potential therapeutic target in clear
cell renal cell carcinoma. Ann Oncol 2013; 24: 343-9; Zhou L, Liu X
D, Sun M, et al. Targeting MET and AXL overcomes resistance to
sunitinib therapy in renal cell carcinoma. Oncogene 2015 Sep. 14.
doi: 10.1038/onc.2015.343; Harshman L C, Choueiri T K. Targeting
the hepatocyte growth factor/c-Met signaling pathway in renal cell
carcinoma. Cancer J 2013; 19: 316-23; Ciamporcero E, Miles K M,
Adelaiye R, et al. Combination strategy targeting VEGF and
HGF/c-met in human renal cell carcinoma models, Mol Cancer Ther
2015; 14: 101-10, Therefore, because cabozantinib targets receptor
tyrosine kinases including MET, MET expression by IHC was
investigated as a potentially predictive biomarker for cabozantinib
in this study population. However, the hazard ratios for PFS and
overall survival suggest that patients experience clinical benefit
with cabozantinib treatment regardless of MET expression level,
which may reflect the broader target profile of cabozantinib. A
limitation of this analysis was that archival tumor tissue was used
in most cases rather than a fresh biopsy obtained before study
treatment initiation, which may have resulted in MET expression
values that were not contemporaneous with the disease state during
study treatment. In addition, approximately one third of the
randomized patients had an unknown MET status due to the fact that
archival tumor tissue was not available.
[0745] The study results support the hypothesis that the target
profile of cabozantinib, which inhibits MET and AXL in addition to
VEGF receptors, may help to overcome resistance to VEGFR
inhibition. Gibney G T, Aziz S A, Camp R L, et al. c-Met is a
prognostic marker and potential therapeutic target in clear cell
renal cell carcinoma. Ann Oncol 2013; 24: 343-9; Gustafsson A,
Martuszewska D, Johansson M, et al. Differential expression of Axl
and Gas6 in renal cell carcinoma reflecting tumor advancement and
survival. Clin Cancer Res 2009; 15: 4742-9; Rankin E B, Fuh K C,
Castellini L, et al. Direct regulation of GAS6/AXL signaling by HIF
promotes renal metastasis through SRC and MET. Proc Natl Acad Sci
USA 2014; 111: 13373-8; Zhou L, Liu X D, Sun M, et al. Targeting
MET and AXL overcomes resistance to sunitinib therapy in renal cell
carcinoma. Oncogene 2015 Sep. 14. doi: 10.1038/onc.2015.343;
Harshman L C, Choueiri T K. Targeting the hepatocyte growth
factor/c-Met signaling pathway in renal cell carcinoma. Cancer J
2013; 19: 316-23; Pinato D J, Chowdhury S, Stebbing J. TAMing
resistance to multi-targeted kinase inhibitors through Axl and Met
inhibition. Oncogene 2015 Oct. 5: doi: 10.1038/onc.2015.374. This
is supported by the observed low incidence of refractory disease
with only 12% of patients experiencing progressive disease as a
best response with cabozantinib treatment. Furthermore,
cabozantinib-treated patients benefited regardless of the duration
of the first prior VEGFR-TKI therapy. The results also suggest that
sequenced VEGFR inhibition can be beneficial for the treatment of
advanced RCC which has also been suggested by the report of a phase
2 study with levantinib. Motzer R J, Hutson T E, Glen H, et al.
Lenvatinib, everolimus, and the combination in patients with
metastatic renal cell carcinoma: a randomized, phase 2, open-label,
multicentre trial. Lancet Oncol 2015; 16: 1473-82. Additional
studies are necessary to clearly define the roles of MET, AXL, and
other targets beyond VEGFR in the clinical activity observed with
cabozantinib in patients with advanced RCC. Future studies may also
include more detailed evaluation of response to first-line therapy
and tumor biopsies at the time of progression to better define the
mechanisms of resistance and the benefits of sequenced VEGFR
inhibition.
[0746] Several VEGFR TKIs have previously been approved for the
treatment of metastatic RCC, and these comprise the mainstay of
present day treatment. Regulatory approval for each of these
(sunitinib, sorafenib, pazopanib and axitinib) was based on an
improvement in PFS over control arms of cytokine (interferon),
placebo, or another TKI (sorafenib) in a randomized phase 3 trial.
Motzer R J, Hutson T E, Tomczak P, et al. Sunitinib versus
interferon alfa in metastatic renal-cell carcinoma. N Engl J Med
2007; 356: 115-24; Escudier B, Eisen T, Stadler W M, et al.
Sorafenib for treatment of renal cell carcinoma: Final efficacy and
safety results of the phase III treatment approaches in renal
cancer global evaluation trial. J Clin Oncol 2009; 27: 3312-8;
Sternberg C N, Davis I D, Mardiak J, et al. Pazopanib in locally
advanced or metastatic renal cell carcinoma: results of a
randomized phase III trial. J Clin Oncol 2010; 28: 1061-8; Rini B
I, Escudier B, Tomczak P, et al. Comparative effectiveness of
axitinib versus sorafenib in advanced renal cell carcinoma (AXIS):
a randomized phase 3 trial. Lancet 2011; 378: 1931-9. The mTOR
inhibitor everolimus, which was used as the comparator arm in this
study, was also approved based on improved PFS when compared to
placebo. Motzer R J, Escudier B, Oudard S, et al. Efficacy of
everolimus in advanced renal cell carcinoma: a double-blind,
randomized, placebo-controlled phase III trial. Lancet 2008; 372:
449-56. None of the pivotal phase 3 trials for these previously
approved agents showed a statistically significant benefit in
overall survival. Improvement in overall survival remains the gold
standard as an endpoint for achieving clinical benefit in patients.
It is therefore highly notable that in this study cabozantinib
treatment resulted in a benefit in overall survival in addition to
improved PFS and objective response rate compared to everolimus in
patients who had progressed on these standard VEGFR-TKI therapies.
The magnitude of overall survival benefit over everolimus
illustrates the high level of clinical activity for cabozantinib in
advanced RCC.
[0747] Recently, the immune checkpoint inhibitor nivolumab
demonstrated an overall survival benefit with an improved response
rate compared to everolimus after prior antiangiogenic therapy, but
no PFS benefit was observed. Motzer R J, Escudier B, McDermott D F,
et al. Nivolumab versus Everolimus in Advanced Renal-Cell
Carcinoma. N Engl J Med 2015; 373: 1803-13. The hazard ratio for
death in the nivolumab study (HR 0.73) was comparable to the hazard
ratio with cabozantinib in this study (HR 0.66); however, the
median overall survival of the comparator arm everolimus differed
(19.6 months in the nivolumab study and 16.5 months in this study),
reflecting the challenges of cross-trial comparison. In the current
study, the observed median overall survival for everolimus was
consistent with that reported in the pivotal RECORD-1 study. Motzer
R J, Escudier B, Oudard S, et al. Phase 3 trial of everolimus for
metastatic renal cell carcinoma: final results and analysis of
prognostic factors. Cancer 2010; 116: 4256-65. The median PFS for
the respective control arms was similar in both trials (4.4 months
in the nivolumab study and 3.9 months in this study). The limits of
publically-available data make it difficult to identify any factors
to explain the differences in overall survival in the control arms
of the two studies.
[0748] In this randomized phase 3 study, treatment with
cabozantinib, an inhibitor of tyrosine kinases including MET, VEGF
receptors, and AXL, was associated with clinically significant
improvement in overall survival, PFS, and objective response rate
compared with everolimus, a standard of care in second-line
advanced RCC. The observed favorable clinical activity of
cabozantinib was applicable to patients of all risk categories and
regardless of prior therapies and extent of tumor burden. Based on
these results, cabozantinib should be considered an important
treatment option for previously-treated patients with advanced
RCC.
Research in Context
[0749] Evidence before this study. In the randomized, phase 3
METEOR trial, cabozantinib, an inhibitor of tyrosine kinases
including MET, VEGF receptors, and AXL, significantly improved
progression-free survival in previously-treated patients with
advanced RCC compared with everolimus. In a literature review up to
Mar. 10, 2016, none of the currently approved therapies had
demonstrated significant benefit for all three efficacy endpoints
of overall survival, progression-free survival, and objective
response rate in a pivotal phase 3 trial in previously-treated
patients with advanced RCC. Research suggested that increased
expression of MET and AXL are associated with a poor prognosis in
RCC patients, and that inhibition of these targets may help to
overcome resistance to VEGF pathway inhibition.
[0750] Added value of this study. In the METEOR phase 3 trial,
treatment with cabozantinib was associated with a significant
reduction in the risk of death, in addition to improving
progression-free survival and the objective response rate compared
with everolimus, a standard of care in second-line advanced RCC.
All patients had documented radiographic progression during or
after prior VEGFR-TKI therapy. The observed clinical benefits were
consistent across various subgroups including MSKCC risk groups,
number of prior VEGFR-TKI therapies, prior immune checkpoint
inhibitor therapy, location and extent of tumor metastases, and
tumor MET expression level. The safety profile of cabozantinib was
consistent with that previously reported.
[0751] Implications of all the available evidence. The observed
improvements in progression-free survival, overall survival, and
objective response rate indicate that cabozantinib should be
considered an important new therapy for previously-treated patients
with advanced RCC. Recently, the immune checkpoint inhibitor
nivolumab also improved overall survival compared with everolimus
in this population, but without improving progression-free
survival. Future research on the optimal use of cabozantinib and
other available therapies may help to provide maximum benefit to
patients with advanced RCC.
Example 2
Quality of Life Outcomes for Cabozantinib Vs Everolimus in Patients
with Metastatic Renal Cell Carcinoma: METEOR Phase III Randomized
Trial
[0752] Purpose: In the Phase 3 METEOR trial, 658 previously-treated
patients with advanced renal cell carcinoma (RCC) were randomly
assigned 1:1 to receive cabozantinib or everolimus. The
cabozantinib arm had improved progression-free survival (PFS),
overall survival (OS), and objective response rate (ORR) compared
with everolimus. Quality of life (QoL) results, an additional
endpoint, are reported here.
[0753] Patients and Methods: Patients completed the 19-item
Functional Assessment of Cancer Therapy-Kidney Symptoms Index
(FKSI-19) and the 5-level EuroQoL-5 Dimensions (EQ-5D-5L)
questionnaires at baseline and throughout the study. The 9-item
FKSI-Disease Related Symptoms (FKSI-DRS) is a subset of FKSI-19.
Data were summarized descriptively and by mixed-effects
repeated-measures analysis (clinically relevant difference was an
effect size .gtoreq.0.3). Time to deterioration (TTD) was defined
as earlier of death, radiographic progressive disease or
.gtoreq.4-point decrease from baseline in FKSI-DRS.
[0754] Results: Questionnaire completion rates remained .gtoreq.75%
through Week 48 in each arm for both instruments. There was no
treatment difference over time for FKSI-19 Total, FKSI-DRS, or EQ
data. Among the individual FKSI-19 items, the only differences were
lower cabozantinib scores for diarrhea, nausea; lower everolimus
scores for shortness of breath. These differences reflect the AE
profile of each drug. Cabozantinib improved TTD overall, with a
notable improvement in patients with bone metastases at
baseline.
[0755] Conclusions: Cabozantinib maintains QoL (FKSI-19 Total,
FKSI-DRS, and EQ-5D) over time in patients with advanced RCC to a
similar extent to everolimus. Compared with everolimus,
cabozantinib extended TTD overall, with a notable improvement in
patients with bone metastases.
Introduction
[0756] Renal cell carcinoma (RCC) is diagnosed in approximately
330,000 individuals worldwide (North America 64,000; Europe
115,000)(Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C,
Rebelo M, et al. Cancer incidence and mortality worldwide: sources,
methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;
136(5):E359-86) and has generally increased in recent years. See
Znaor A, Lortet-Tieulent J, Laversanne M, Jemal A, Bray F.
International Variations and Trends in Renal Cell Carcinoma
Incidence and Mortality. Eur Urol. 2015; 67(3):519-530.; Cella D.
Quality of life in patients with metastatic renal cell carcinoma:
the importance of patient-reported outcomes. Cancer Treat Rev.
2009; 35(8):733-7. It affects more men than women; peak incidence
occurs between 60-70 years of age. Many patients present with
advanced or unresectable disease at initial diagnosis. QoL in
patients with advanced RCC is impacted by frequent disease-related
symptoms (such as fatigue, weakness, bone pain, hematuria, weight
loss, and shortness of breath) and treatment-related side effects
(Cella D. Quality of life in patients with metastatic renal cell
carcinoma: the importance of patient-reported outcomes. Cancer
Treat Rev. 2009; 35(8):733-7; Palapattu G S, Kristo B, Rajfer J.
Paraneoplastic syndromes in urologic malignancy: the many faces of
renal cell carcinoma. Rev Urol. 2002; 4(4):163-70).
[0757] First-line systemic standard-of-care treatments for patients
with advanced clear cell RCC are the VEGF receptor tyrosine kinase
inhibitors (VEGFR-TKIs) sunitinib and pazopanib. Second-line
standard-of-care therapies include the VEGFR-TKIs cabozantinib,
axitinib, and sorafenib; the mTOR inhibitor everolimus; and the
PD-1 checkpoint inhibitor nivolumab (NCCN. National Comprehensive
Cancer Network Guidelines in Oncology. Kidney Cancer. Version 2
2016. Nov. 24, 2015; Ljungberg B, Bensalah K, Canfield S, Dabestani
S, Hofmann F, Hora M, et al. EAU guidelines on renal cell
carcinoma: 2014 update. Eur Urol. 2015; 67(5):913-24; Powles T,
Staehler M, Ljungberg B, Bensalah K, Canfield S E, Dabestani S, et
al. Updated EAU Guidelines for Clear Cell Renal Cancer Patients Who
Fail VEGF Targeted Therapy. Eur Urol. 2016; 69(1):4-6; Signorovitch
J E, Vogelzang N J, Pal S K, Lin P L, George D J, Wong M K et al.
Comparative effectiveness of second-line targeted therapies for
metastatic renal cell carcinoma: synthesis of findings from two
multi-practice chart reviews in the United States. Curr Med Res
Opin. 2014; 30(11):2343-53).
[0758] Cabozantinib is an oral inhibitor of tyrosine kinases,
including MET, VEGFR, and AXL (Yakes F M, Chen J, Tan J, Yamaguchi
K, Shi Y, Yu P, et al. Cabozantinib (XL184), a Novel MET and VEGFR2
Inhibitor, Simultaneously Suppresses Metastasis, Angiogenesis, and
Tumor Growth. Mol Cancer Ther. 2011; 10:2298-308). Upregulation of
MET and AXL in clear-cell RCC is a consequence of von Hippel-Lindau
protein dysfunction and has been implicated in tumor progression
and VEGFR-TKI resistance in preclinical studies and has been
associated with a poor prognosis in patients with advanced RCC
(Gibney G T, Aziz S A, Camp R L, Conrad P, Schwartz B E, Chen C R,
et al. c-Met is a prognostic marker and potential therapeutic
target in clear cell renal cell carcinoma. Ann Oncol. 2013;
24(2):343-9; Gustafsson A, Martuszewska D, Johansson M, Ekman C,
Hafizi S, Ljungberg B, et al. Differential expression of Axl and
Gas6 in renal cell carcinoma reflecting tumor advancement and
survival. Clin Cancer Res. 2009; 15(14):4742-9; Rankin E B, Fuh K
C, Castellini L, Viswanathan K, Finger E C, Diep A N, et al. Direct
regulation of GAS6/AXL signaling by HIF promotes renal metastasis
through SRC and MET. Proc Natl Acad Sci USA. 2014; 111(37):13373-8;
Zhou L, Liu X D, Sun M, Zhang X, German P, Bai S, et al. Targeting
MET and AXL overcomes resistance to sunitinib therapy in renal cell
carcinoma. Oncogene. 2016; 35(21):2687-97; Harshman L C, Choueiri T
K. Targeting the hepatocyte growth factor/c-Met signaling pathway
in renal cell carcinoma. Cancer J. 2013; 19(4):316-23; Pinato D J,
Chowdhury S, Stebbing J. TAMing resistance to multi-targeted kinase
inhibitors through AxI and Met inhibition. Oncogene. 2016;
35(21):2684-6). Cabozantinib gained regulatory approval in the US
and in Europe as a second-line treatment for patients with advanced
RCC after prior therapy with an antiangiogenic drug based on
improvements in the randomized Phase 3 METEOR trial against
everolimus for progression-free survival (PFS; primary endpoint)
and the two secondary endpoints of overall survival (OS) and
objective response rate (ORR)(Choueiri T K, Escudier B, Powles T,
Mainwaring P N, Rini B I, Donskov F, et al. Cabozantinib versus
Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 2015;
373(19):1814-23; Choueiri T K, Escudier B, Powles T, Tannir N M,
Mainwaring P N, Rini B I, et al. Cabozantinib versus everolimus in
advanced renal cell carcinoma (METEOR): final results from a
randomized, open-label, phase 3 trial. Lancet Oncol. 2016;
17(7):917-27). Median PFS was 7.4 months in the cabozantinib arm vs
3.8 months in the everolimus arm (hazard ratio [HR] 0-58 [95%
confidence intervals {CI}: 0-45, 0-74]; p<0-0001) and ORR was
17% vs 3% (p<0-0001), both endpoints per independent radiology
review. Median OS was 21-4 months (95% CI: 18-7, not estimable) vs
16-5 months (95% CI: 14-7, 18-8) (HR 0-66 [95% CI: 0-53, 0-83];
p=0-0003). Quality of life was an additional endpoint in this study
and these results are reported below.
Patients and Methods
[0759] Eligibility and Study Treatments. METEOR is a randomized,
open-label, Phase 3 study with patients enrolled at 173 hospital
and outpatient clinics in 26 countries. Patients 18 years or older
with advanced or metastatic RCC and a clear-cell histology were
eligible for enrollment if they had measurable disease per Response
Evaluation Criteria in Solid Tumors (RECIST version 1.1)(Eisenhauer
et al 2011) had received at least one previous VEGFR-TKI (there was
no limit to the number of previous treatments), and had disease
progression during or within 6 months of the most recent VEGFR-TKI
treatment and within 6 months before randomization. Patients were
required to have a Karnofsky performance status score of
.gtoreq.70% and adequate organ function, based on standard
laboratory tests including hematology, serum chemistry, lipids,
coagulation, thyroid function, and urinalysis. Asymptomatic
patients with stable brain metastases were eligible. Patients with
previous mTOR inhibitor therapy, including everolimus, were not
eligible for the study nor were patients with uncontrolled
hypertension or clinically significant cardiovascular,
gastrointestinal, wound healing, or infectious comorbidities. The
study adhered to the Good Clinical Practice guidelines and the
Declaration of Helsinki. The institutional review board or ethics
committee of the participating centers approved the study protocol.
All patients provided written informed consent.
[0760] Patients were randomized (1:1) to receive either
cabozantinib or everolimus. Randomization was stratified by the
number of prior VEGFR-TKI treatments (1 or .gtoreq.2) and Memorial
Sloan Kettering Cancer Center (MSKCC) risk groups (favorable,
intermediate, or poor) for previously-treated RCC (Motzer R J,
Bacik J, Schwartz L H, Reuter V, Russo P, Marion S, et al.
Prognostic Factors for Survival in Previously Treated Patients With
Metastatic Renal Cell Carcinoma. J Clin Oncol. 2004; 22:454-463).
Study treatment was assigned centrally with an interactive voice
and web response system. Patients and investigators were not masked
to study treatment to allow appropriate management of adverse
events (AEs).
[0761] Cabozantinib was given orally 60 mg once-daily (qd) and
everolimus was given orally 10 mg qd. Treatment interruptions and
reductions were allowed to manage AEs. Cabozantinib could be dose
reduced to 40 mg and then 20 mg; everolimus could be dose reduced
to 5 mg and then 2.5 mg. Patients with clinical benefit could
continue study treatment beyond radiographic progression at the
discretion of the investigator. On-study crossover between
treatment arms was not permitted.
[0762] Radiographic tumor imaging assessments occurred regularly
every 8-12 weeks throughout the study. Assessment of AEs were
performed throughout the study. Patients had a 30-day
post-treatment visit with subsequent survival follow-up every 8
weeks. Efficacy and safety evaluations in this study have been
previously described (Choueiri T K, Escudier B, Powles T,
Mainwaring P N, Rini B I, Donskov F, et al. Cabozantinib versus
Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 2015;
373(19):1814-23; Choueiri T K, Escudier B, Powles T, Tannir N M,
Mainwaring P N, Rini B I, et al. Cabozantinib versus everolimus in
advanced renal cell carcinoma (METEOR): final results from a
randomized, open-label, phase 3 trial. Lancet Oncol. 2016;
17(7):917-27).
[0763] QoL Assessments. QoL was measured by using two validated
patient self-reported instruments: the Functional Assessment of
Cancer Therapy-Kidney Symptom Index-19 item (FKSI-19) and EuroQol
Group's EQ-5D-5L questionnaires. Patients were required to complete
the QoL questionnaires before any assessments at each clinic visit
prior to the first dose, every 4 weeks through Week 25, every 8
weeks thereafter for the first year, then every 12 weeks
thereafter. The QoL assessments were conducted per protocol prior
to the patient knowing the results of their next tumor assessment.
These assessments were performed regardless of whether study
treatment was given, reduced, interrupted, or discontinued until
the date of the last tumor imaging assessment. Questionnaires were
provided on paper in the patient's own language.
[0764] FKSI-19. The FKSI-19 instrument is a 19-item self-reported
questionnaire with a total score and four subscales that assesses
disease-related symptoms (DRS), treatment side effects, and
function/well-being associated with advanced kidney cancer. It
queries symptom severity and interference in activity and general
health perceptions (Rao D, Butt Z, Rosenbloom S, Robinson D Jr, Von
Roenn J, Kuzel T M, Cella D. A Comparison of the Renal Cell
Carcinoma-Symptom Index (RCC-SI) and the Functional Assessment of
Cancer Therapy-Kidney Symptom Index (FKSI). J Pain Symptom Manage.
2009; 38(2):291-8; Rothrock N E, Jensen S E, Beaumont J L,
Abernethy A P, Jacobsen P B, Syrjala K, Cella D. Development and
initial validation of the NCCN/FACT symptom index for advanced
kidney cancer. Value Health. 2013; 16(5):789-96). The FKSI-19
comprises four sub-scales (DRS-Physical, DRS-Emotional, Treatment
Side Effects, and Function/Well Being; Table 2.1). Each of the
items is scored on a 5-point scale from 0 (not at all) to 4 (very
much). Higher FKSI-19 scores indicate improvement. The FKSI-19
ensures content validity congruent with FDA Guidance (FDA. Guidance
for Industry. Patient-Reported Outcome Measures: Use in Medical
Product Development to Support Labeling Claims. December 2009). and
was developed from a previous 9-item DRS version (FKSI-DRS; lack of
energy, pain, losing weight, fatigue, short of breath, fevers, bone
pain, coughing, blood in urine). The FKSI-19 includes selected
treatment side effects that are important to the patient and
physician.
TABLE-US-00021 TABLE 2.1 Treatment Differences in FKSI-19 and four
subscales, FKSI-DRS, EQ-5D-VAS, and EQ-Index, Repeated Measures
Change from Baseline Analysis (ITT Population) LSMean Effect
Cabozantinib Everolimus Size.sup.a DRS-Physical -1.093 -1.386 0.046
Lack of energy -0.244 -0.207 -0.033 Pain 0.125 0.067 0.052 Losing
weight -0.533 -0.301 -0.21 Fatigued -0.325 -0.305 -0.017 Short of
breath 0.029 -0.271 0.30 Fevers 0.056 -0.021 0.13 Bone pain 0.049
0.057 -0.008 Coughing 0.237 -0.059 0.28 Weak all over -0.281 -0.265
-0.015 Blood in my urine 0.005 -0.001 0.023 Good appetite -0.166
0.181 -0.23 Sleeping well 0.018 -0.152 0.12 DRS-Emotional 0.398
0.393 0.004 Worry condition worsen 0.398 0.393 0.004 Treatment Side
Effects -2.416 -0.814 -0.62 Nausea -0.236 0.069 -0.34 Diarrhea
-1.280 -0.326 -0.77 Side effects of treatment -0.850 -0.523 -0.24
Function/Well-Being -0.230 -0.169 -0.019 Able to work -0.151 -0.101
-0.037 Enjoy life -0.017 -0.014 -0.002 Content with quality life
-0.035 -0.017 -0.014 FKSI-19 (19-item) Total Score -3.483 -2.214
-0.13 FKSI-DRS (9-item) -0.52 -0.93 0.087 EQ-VAS -1.32 -1.27 -0.003
EQ-Index -0.02 -0.02 -0.009 DRS, disease-related symptoms; EQ-VAS,
EuroQol Visual Analogue Scale; FKSI, Functional Assessment of
Cancer Therapy-Kidney Cancer Symptom Index; ITT, intent-to-treat;
LSMean, least squares mean. A positive mean change (higher score)
indicates improved quality of life status. .sup.aEffect size =
treatment difference in mean change from baseline scores/pooled SD
for both groups for baseline values. Effect sizes .gtoreq. 0.3 for
treatment arm comparisons were regarded as likely to be clinically
relevant. Positive effect size values favor cabozantinib.
[0765] FIG. 2.1 depicts the quality of life instruments and quality
of life assessment schedule. The items from the earlier FKSI-DRS
(9-item) version are included within the FACT Kidney Symptom Index
(FKSI-19). FKSI-19 evaluates kidney cancer specific quality of
life. A total of 19 items are grouped into four sub-classes and
each item is scored on a four-point scale from 0 (not at all) to 4
(very much). Higher scores indicate better quality of life.
[0766] The quality of life assessment schedule is a questionnaire
completed by a patient prior to assessment.
[0767] FKSI-19 norms for the general US population have been
calculated (Butt Z, Peipert J, Webster K, Chen C, Cella D. General
population norms for the Functional Assessment of Cancer
Therapy-Kidney Symptom Index (FKSI). Cancer. 2013; 119(2):429-37).
The FKSI instrument has been utilized in other pivotal studies in
RCC (Cella D, Grunwald V, Nathan P, Doan J, Dastani H, Taylor F, et
al. Quality of life in patients with advanced renal cell carcinoma
given nivolumab versus everolimus in CheckMate 025: a randomized,
open-label, phase 3 trial. Lancet Oncol. 2016; 17(7):994-1003;
Motzer R J, Hutson T E, Cella D, Reeves J, Hawkins R, Guo J, et al.
Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N
Engl J Med. 2013; 369(8):722-31; Motzer R J, Escudier B, Tomczak P,
Hutson T E, Michaelson M D, Negrier S, et al Axitinib versus
sorafenib as second-line treatment for advanced renal cell
carcinoma: overall survival analysis and updated results from a
randomized phase 3 trial. Lancet Oncol 2013; 14:552-562; Motzer R
J, Escudier B, Oudard S, Hutson T E, Porta C, Bracarda S, et al.
Efficacy of everolimus in advanced renal cell carcinoma: a
double-blind, randomized, placebo-controlled phase III trial.
Lancet. 2008; 372(9637):449-56; Cella D, Michaelson M D, Bushmakin
A G, Cappelleri J C, Charbonneau C, Kim S T, et al. Health-related
quality of life in patients with metastatic renal cell carcinoma
treated with sunitinib vs interferon-alpha in a phase III trial:
final results and geographical analysis. Br J Cancer. 2010;
102(4):658-64).
[0768] EQ-5D-5L. The standardized measure of health status
EQ-5D-5L, developed by the EuroQol, was also used in this study in
order to measure generic health status (Herdman M, Gudex C, Lloyd
A, Janssen M, Kind P, Parkin D, et al. Development and preliminary
testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual
Life Res. 2011; 20(10):1727-36). It comprises five functional and
symptom dimensions: mobility, self-care, usual activities,
pain/discomfort, and anxiety/depression. Levels indicate increasing
severity from Level 1 (no problem) to Levels 2 through 5 (mild
problem to extreme problem). The digits from the 5 dimensions were
converted into a single population-based index value normalized
across the nine countries in the study for which index value sets
were available (van Hout B, Janssen M F, Feng Y S, Kohlmann T,
Busschbach J, Golicki D, et al. Interim scoring for the EQ-5D-5L:
mapping the EQ-5D-5L to EQ-5D-3L value sets. Value Health. 2012;
15(5):708-15). Index values range from 0 to 1 and a higher index
score indicates better health. Patients also completed a 20-cm
vertical visual assessment scale (VAS) scored from 0 ("worst health
you can imagine") to 100 ("best health you can imagine"). A prior
(3-level) version of the EQ-5D instrument had been evaluated in a
study of pazopanib vs placebo (Cella D, Pickard A S, Duh M S,
Guerin A, Mishagina N, Antras L, et al. Health-related quality of
life in patients with advanced renal cell carcinoma receiving
pazopanib or placebo in a randomized phase III trial. Eur J Cancer.
2012; 48(3):311-23) and in the NCT83889 study of sunitinib vs
interferon (Cella D. Quality of life in patients with metastatic
renal cell carcinoma: the importance of patient-reported outcomes.
Cancer Treat Rev. 2009; 35(8):733-7).
[0769] Statistical Analysis. The QoL analyses were performed on the
intention-to-treat (ITT) population with the same data cutoff date
(May 22, 2015) as the primary PFS endpoint (Choueiri T K, Escudier
B, Powles T, Mainwaring P N, Rini B I, Donskov F, et al.
Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma. N
Engl J Med. 2015; 373(19):1814-23; Choueiri T K, Escudier B, Powles
T, Tannir N M, Mainwaring P N, Rini B I, et al. Cabozantinib versus
everolimus in advanced renal cell carcinoma (METEOR): final results
from a randomized, open-label, phase 3 trial. Lancet Oncol. 2016;
17(7):917-27). OS analyses used a Dec. 31, 2015 cutoff date. All
available data were included in the analyses, no data were imputed.
The questionnaire completion rate was calculated as number
completed/number expected at that timepoint.
[0770] Descriptive statistics were used to summarize QoL scores
over time for each treatment arm. In addition, a pre-specified
repeated-measures mixed effects model was used to compare changes
from baseline between the two treatment arms. The model included
the outcome variable of QoL score change from baseline. The
predictors (fixed effects) were the baseline scores, treatment
arms, and visit. The individual subject nested within the planned
treatment arm was the random effect. No adjustment was made for
multiplicity. Effect sizes in the range 0.2 to <0.5 are
generally considered to be small, for this study an effect size for
treatment arm comparisons of .gtoreq.0.3 was regarded as likely to
be clinically relevant (Sloan J A, Cella D, Hays R D. Clinical
significance of patient-reported questionnaire data: another step
toward consensus. J Clin Epidemiol. 2005; 58(12):1217-9; Yost K J,
Eton D T. Combining distribution- and anchor-based approaches to
determine minimally important differences: the FACIT experience.
Eval Health Prof. 2005; 28(2):172-91).
[0771] To assess the effect of patient dropout, post-hoc piecewise
linear growth curve sensitivity analyses were undertaken using a
mixed-effect regression model. Fixed effects included baseline
score, randomization stratification factors, treatment arm, time (a
continuous variable) and the interaction between treatment arm and
time. Random effects included intercept and slope. The mean
trajectory of each arm based on Early (before Week 25), Median
(Weeks 25-33), and Late (Week 41 and after) dropout tertiles was
estimated. Dropout was defined as the last available analyzable
score.
[0772] Time to deterioration (TTD; the earlier of death,
radiographic disease progression (rPD), or .gtoreq.4-point decrease
from baseline in the 9-item FKSI-DRS) was a post-hoc analysis. The
TTD was repeated as a sensitivity analysis using a .gtoreq.3-point
decrease.
[0773] Finally, a post-hoc analysis of the effect of FKSI-DRS
scores on OS was performed in two groups of patients (.gtoreq.,
<median FKSI-DRS at baseline). The same Kaplan-Meier method was
used as in a previous OS analysis (Choueiri T K, Escudier B, Powles
T, Tannir N M, Mainwaring P N, Rini B I, et al. Cabozantinib versus
everolimus in advanced renal cell carcinoma (METEOR): final results
from a randomized, open-label, phase 3 trial. Lancet Oncol. 2016;
17(7):917-27).
Results
[0774] Baseline Characteristics. A total of 658 patients were
randomly assigned and included in the intent-to-treat (ITT)
analysis (FIG. 1.14). At the cutoff date for the QoL analysis 40%
of patients in the cabozantinib arm and 21% in the everolimus arm
were still on study treatment. The incidence of discontinuation due
to a primary reason of AE (excluding disease progression) was
similar (10%) in each arm.
[0775] Baseline characteristics were similar in each arm (Table
2.2). Mean age was 62 years in the cabozantinib arm and 61 in the
everolimus arm; approximately 75% of patients were male. FKSI-19
and FKSI-DRS (9-item) mean scores in each arm were similar to the
US Adult Population values of 59.8 and 29.5, respectively (Butt Z,
Peipert J, Webster K, Chen C, Cella D. General population norms for
the Functional Assessment of Cancer Therapy-Kidney Symptom Index
(FKSI). Cancer. 2013; 119(2):429-37).
TABLE-US-00022 TABLE 2.2 Patient Demographics and Baseline
Characteristics (ITT Population) Cabozantinib Everolimus Patient
Characteristic N = 330 N = 328 Age, mean (range), years 61.7 (32,
86) 61.1 (31, 84) Sex, n (%).sup.a Male 253 (77) 241 (73) Female 77
(23) 86 (26) Race, n (%).sup.a White 269 (82) 263 (80) Asian 21
(6.4) 26 (7.9) Black or African American 6 (1.8) 3 (0.9) Other 19
(5.8) 13 (4.0) Not reported 15 (4.5) 22 (6.7) Enrollment per
geographic region, n (%) Europe 167 (51) 153 (47) North America 118
(36) 122 (37) Asia Pacific 39 (12) 47 (14) Latin America 6 (1.8) 6
(1.8) Karnofsky Performance Status, n (%) .gtoreq.80 301 (91) 306
(93) 70 29 (8.8) 22 (6.7) Randomization stratification factors, n
(%) Prior VEGFR-TK1 1 233 (71) 231 (70) .gtoreq.2 97 (29) 97 (30)
MSKCC risk group.sup.Motzer et al 2004 Favorable 150 (45) 150 (46)
Intermediate 137 (42) 136 (41) Poor 42 (13) 42 (13) Bone metastases
per IRC 77 (23) 65 (20) FKSI-19 Total score, n = 324 n = 313 mean
(SD) 56.7 (10.51) 57.1 (10.17) FKSI-DRS (9-item) n = 324 n = 313
score, mean (SD) 29.1 (5.08) 29.3 (4.92) EQ-Index (in countries n =
188 n = 181 in which index was 0.77 (0.240) 0.80 (0.184)
validated), mean (SD) EQ-VAS, mean (SD) n = 323 n = 314 73.6
(18.62) 74.1 (17.50) Abbreviations: DRS, disease-related symptoms;
EQ-VAS, EuroQol Visual Analogue Scale; FKSI-19, Functional
Assessment of Cancer Therapy-Kidney Symptom Index-19 item; IRC,
Independent Review Committee; MSKCC, Memorial Sloan-Kettering
Cancer Center; SD, standard deviation; VEGFR, vascular endothelial
growth factor receptor; TKI, tyrosine kinase inhibitor .sup.aSex
and race were missing for one patient. Patients could report more
than one race.
[0776] Efficacy outcomes for the study are depicted in Table
2.3.
TABLE-US-00023 TABLE 2.3 Cabozantinib Everolimus Hazard Outcome (N
= 30) (N = 328) Ratio.sup.a P-Value.sup.b PFS per IRC,.sup.c 7.4
3.9 0.51 <0.0001 mo Median (6.6, 9.1) (3.7, 5.1) (0.41, 0.62)
(95% CI) OS,.sup.d mo 21.4 16.5 0.66 <0.00026 Median (18.7, NE)
(14.7, 18.8) (0.53, 0.83) (95% CI) ORR per 17 3 NA <0.0001
IRC,.sup.c mo (13, 22) (2, 6) Median (95% CI) CI, confidence
interval; IRC, independent radiology committee; ITT, intent to
treat; mo, months; NA, not applicable; NE, notestimable; ORR,
objective response rate; OS, overall survival; PFS, progression
free survival .sup.aEstimated using Cox proportional hazard model
adjusted for stratification factors; .sup.bP-value determined using
stratified log-rank test (PFS and OS) and chi squared test (ORR);
.sup.cMay 22, 2015 cutoff date; .sup.dDec. 31, 2015 cutoff
date.
[0777] Questionnaire Completion Rate. The questionnaire completion
rates (number completed/expected at each timepoint) were high and
similar in each treatment arm for both instruments. At baseline the
rates for the FKSI-19 (EQ-5D) were 98% (96%) and 95% (95%) in the
cabozantinib and everolimus arms, respectively, and remained
.gtoreq.75% through Week 49 in each arm for both instruments.
[0778] FKSI Assessments. FKSI-19 total scores over time are
depicted in FIG. 2.2A and FIG. 2.2B. There were no apparent
differences over time between the two treatment arms based on
descriptive summaries for the FKSI-19 Total or 9-item FKSI-DRS or
for the EQ instrument (data not shown). There was also no treatment
difference (i.e., effect size <0.3) based on a repeated-measures
mixed effect model change from baseline analysis for FKSI-19 Total
or 9-item FKSI-DRS (Table 2.3). Among the 19 individual items, the
only differences based on effect size were lower scores in
cabozantinib arm for diarrhea and nausea and lower scores in the
everolimus arm for shortness of breath.
[0779] EQ-5D-5L Assessments. There were no apparent differences
over time between the two treatment arms (ie, effect size <0.3)
based on a repeated-measures change from baseline analysis for
EQ-Index or EQ-VAS (Table 2.3). There was no apparent treatment
difference based on descriptive summaries over time for EQ-Index or
EQ-VAS (data not shown).
[0780] Sensitivity Analyses. Post-hoc growth curve sensitivity
analyses in Table 2.4 show that there was an inconsistent effect
primarily for the intercept (which represents the initial treatment
difference at Week 4) across the three tertiles (Early, Median, and
Late Dropout). Additional analyses are planned to further explore
this observation.
TABLE-US-00024 TABLE 2.4 Growth Curve Analysis: Estimated Treatment
Difference in Change from Baseline By Dropout Tertile (ITT
Population) Early Median Late Dropout Dropout Dropout (before
(Weeks (Week 41 Parameter Week 24) 25-33) or later) FKSI-19 Total
Cabo vs Evero Slope 0.131 0.141 0.082 Cabo vs Evero 0.241 -2.003
-5.141 Intercept.sup.a Evero Intercept.sup.a -3.643 -1.838 1.105
FKSI-DRS (9-item) Cabo vs Evero Slope 0.037 0.094 0.046 Cabo vs
Evero 1.445 -0.313 -1.307 Intercept.sup.a Evero Intercept.sup.a
-2.002 -0.843 0.453 EQ-Index Cabo vs Evero Slope 0.005 0.003 0.003
Cabo vs Evero 0.020 -0.033 -0.090 Intercept.sup.a Evero
Intercept.sup.a -0.046 -0.018 0.033 EQ-VAS Cabo vs Evero Slope
0.498 0.146 0.134 Cabo vs Evero -1.933 -0.352 -4.749
Intercept.sup.a Evero Intercept.sup.a -2.474 -1.181 1.012 Cabo,
cabozantinib; evero, everolimus. Positive treatment differences
favor cabozantinib. .sup.aChange at Week 4 (first post-baseline
timepoint). For everolimus intercept data, positive values indicate
better quality of life and negative values indicate worse quality
of life.
[0781] Table 2.5 summarizes changes from baseline in QOL outcomes
by repeated measurement analysis.
TABLE-US-00025 TABLE 2.5 Changes from Baseline In Qol Outcomes,
Repeated Measures Analysis Scale (range) Subscale Items which met
Least Squares Mean Effect effect size criterion Cabozantinib
Everolimus Size* FKSI-19 Total -3.483 -2.214 -0.13 Score (0-76)
DRS-Physical (0-48) -1.093 -1.386 0.046 Short of breath (0-4) 0.029
-0.271 0.30.sup.b DRS-Emotional (0-4) 0.398 0.393 0.004 Treatment
Side -2.416 -0.814 -0.62.sup.b Effects (0-12) Nausea (0-4) -0.236
0.069 -0.34.sup.b Diarrhea (0-4) -1.28 -0.326 -0.77.sup.b
Function/Well-being -0.230 -0.169 -0.019 (0-12) FKSI-DRS (9-item)
-0.52 -0.93 0.087 (0-36) EQ VAS (0-100) -1.32 -1.27 -0.003 EQ Index
(0-1) -0.02 -0.02 -0.009 DRS, disease-related symptoms; EQ,
EuroQol; FKS1, FACT Kidney Symptom Index; Qol, quality of life; SD,
standard deviation; VAS, visual analogue scale. Higher scores
indicated improved QOL status. .sup.aEffect size = treatment
difference in mean change from baseline scores/pooled SD for both
groups for baseline values. Positive effect size values favor
cabozantinib. .sup.bEffect sizes .gtoreq. 0.3 for treatment arm
comparisons were regarded as likely to be clinically relevant.
[0782] Time to deterioration (TTD). There was a notable decrease in
QoL scores compared with baseline at the time of rPD per
investigator. Progressive disease was the most frequent reason for
study treatment discontinuation. Cabozantinib treatment improved
TTD (earlier of death, rPD, .gtoreq.4-point decrease from baseline
in FKSI-DRS) compared with everolimus: median TTD 5.5 vs 3.7 mo
(p<0.0001; FIG. 2.3 (and Table 2.6). In a subgroup analysis,
there was a pronounced TTD improvement with cabozantinib treatment
in patients with bone metastases: median TTD 5.6 vs 1.9 mo
(p=0.0003; FIG. 2.4 and Table 2.6).
TABLE-US-00026 TABLE 2.6 Time to Deterioration (ITT Population)
Cabozantinib Everolimus HR Median (mo) Median (mo) (95% CI).sup.a
p-value.sup.b Overall (earlier 5.5 3.7 0.65 (0.54, 0.78) <0.0001
of death, rPD, .gtoreq.4-point FKSI- DRS decrease from BL) Bone
metastases per IRC at BL Yes 5.6 1.9 0.49 (0.33, 0.72) 0.0003 No
5.5 3.8 0.69 (0.56, 0.85) 0.0004 BL, baseline; CI, confidence
interval; HR, hazard ratio; IRC, Independent Review Committee; rPD,
radiographic progressive disease .sup.aUnstratified HRs are from
the Cox Proportional Hazards model .sup.bUnstratified log-rank
test
[0783] QoL as a Prognostic Factor for OS. Baseline FKSI-DRS
(9-item) scores higher than the median population values were
associated with improved OS in both treatment arms, as depicted in
FIG. 1.16). HRs for OS favored the cabozantinib arm regardless of
baseline QoL.
Discussion
[0784] As previously reported (Choueiri T K, Escudier B, Powles T,
Mainwaring P N, Rini B1, Donskov F, et al. Cabozantinib versus
Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 2015;
373(19):1814-23; Choueiri T K, Escudier B, Powles T, Tannir N M,
Mainwaring P N, Rini B I, et al. Cabozantinib versus everolimus in
advanced renal cell carcinoma (METEOR): final results from a
randomized, open-label, phase 3 trial. Lancet Oncol. 2016;
17(7):917-27) the METEOR Phase 3 trial demonstrated that
cabozantinib, an oral inhibitor of tyrosine kinases including MET,
VEGFR, and AXL, improved key clinical endpoints of PFS, OS, and ORR
compared with everolimus in patients with advanced RCC who had
received a prior VEGFR-TKI. The improved efficacy for cabozantinib
was demonstrated across all pre-specified subgroups. We now report
the QoL, an additional endpoint in this trial, which was assessed
using standardized instruments (FKSI-19 and EQ-5D-5L). This is the
first head-to-head QoL assessment against an mTOR inhibitor
comparator in a Phase 3 setting of advanced RCC patients eligible
for second-line treatment.
[0785] The FKSI-19 instrument was developed to allow the impact of
specific treatment-related side effects to be assessed. There was
no clinically meaningful difference between treatment arms in
FKSI-19 Total scores. Among the 19 individual items, the observed
treatment differences (worse diarrhea and nausea for cabozantinib,
worse shortness of breath for everolimus) reflect the different
safety profiles of each agent. Management of treatment-related AEs
in this study may be considered to be reflective of real-world
conditions in that this was an open-label trial. Physicians should
aim to proactively manage side effects, for example by
administration of antidiarrheal agents at the first sign of
diarrhea. Tolerability of study treatment, based on the low
proportion of patients who discontinued study treatment due to AEs
(.about.10% of patients in each arm), was similar for each study
treatment and supports the role of early management of AEs. Of
note, there was a low rate of study treatment discontinuation due
to diarrhea (0.9% of patients in each arm).
[0786] The earlier developed (9-item) FKSI-DRS instrument was
intended to examine the effect of study treatment on
disease-related symptoms rather than treatment-related adverse
effects. Consistent with the 19-item scale, no clinically
meaningful treatment difference in QoL was seen for cabozantinib as
compared with everolimus. Of note, the previous placebo-controlled
study for everolimus showed no difference in FKSI-DRS over time
(Beaumont J L, Butt Z, Baladi J, Motzer R J, Haas T, Hollaender N,
et al. Patient-reported outcomes in a phase iii study of everolimus
versus placebo in patients with metastatic carcinoma of the kidney
that has progressed on vascular endothelial growth factor receptor
tyrosine kinase inhibitor therapy. Oncologist. 2011;
16(5):632-40).
[0787] QoL decreased notably in both treatment arms at the time of
investigator-determined rPD highlighting the negative impact of
disease progression on QoL, and the benefit of extending PFS. The
prolongation of TTD further supports the overall clinical benefit
of cabozantinib treatment in addition to improving PFS, ORR, and
OS. The majority of patients in the cabozantinib arm (75%, compared
with 48% in the everolimus arm) experienced reduction in measurable
tumor lesion size which may be reflected in the improvement in TTD
with cabozantinib treatment. The results of the generic EQ-5D
(health index and patient-based VAS) instrument support the
findings from the overall FKSI-19 and FKSI-DRS scales of no
clinically relevant treatment difference between the two study
arms. Finally, the effect of baseline QoL on OS has been
demonstrated in this study: higher baseline QoL was associated with
improved OS in both treatment arms. A similar correlation has been
observed in another RCC study (Cella D, Grunwald V, Nathan P, Doan
J, Dastani H, Taylor F, et al. Quality of life in patients with
advanced renal cell carcinoma given nivolumab versus everolimus in
CheckMate 025: a randomized, open-label, phase 3 trial. Lancet
Oncol. 2016; 17(7):994-1003).
[0788] The study used an open-label design so patients and
caregivers were aware of their study treatment allocation which
could potentially lead to an impact on QoL evaluations. However,
this may be more of a concern with unequal randomization whereas
this trial had equal randomization to active treatments. In
addition, QoL assessments were scheduled per protocol prior to the
patient knowing the results of their most recent radiographic tumor
assessment. This was also a multinational trial with no adjustment
for by-country differences. However, this is unlikely to be
important in a randomized trial, and key efficacy outcomes (PFS,
OS) have been shown to be similar by region (Choueiri T K, Escudier
B, Powles T, Mainwaring P N, Rini B I, Donskov F, et al.
Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma. N
Engl J Med. 2015; 373(19):1814-23; Choueiri T K, Escudier B, Powles
T, Tannir N M, Mainwaring P N, Rini B I, et al. Cabozantinib versus
everolimus in advanced renal cell carcinoma (METEOR): final results
from a randomized, open-label, phase 3 trial. Lancet Oncol. 2016;
17(7):917-27).
[0789] Use of a mixed effect repeated measures model reduces the
potential for bias resulting from dropouts i.e., all available data
are used: if a score is missing, it has no effect on other scores
from that same patient. In terms of validity of study results, a
lack of treatment difference has been demonstrated in both
unadjusted and the pre-specified mixed effects repeated measures
modelled data. However, post-hoc growth curve sensitivity analyses
suggest heterogeneity of the treatment difference (primarily in the
intercept, which represents the initial treatment difference at
Week 4) across the Early, Median, and Late Dropout tertiles. Of
note, results adjusting for non-random dropouts using a technique
such as pattern mixture modeling which identifies a weighted
average effect across dropout groups may be challenging to
interpret due to these time-based differences. Based on these
results additional analyses are planned to further explore this
observation.
[0790] In conclusion, the METEOR trial showed that QoL was
maintained over time to a similar extent in both the cabozantinib
and everolimus arms. The totality of results for PFS, OS, and ORR
shows that cabozantinib has a favorable clinical benefit compared
with everolimus and is considered a new standard of care for
previously treated patients with advanced RCC.
Example 3
Efficacy of Cabozantinib (Cabo) Vs Everolimus (Eve) by Metastatic
Site and Tumor Burden in Patients (Pts) with Advanced Renal Cell
Carcinoma (RCC) in the Phase 3 METEOR Trial
[0791] Background: High tumor burden (TB) in pts with RCC is
associated with poor prognosis (Iacovelli BJU Int 2012). In the
Phase 3 METEOR trial (NCTO1865747) in advanced RCC after prior
vascular endothelial growth factor receptor (VEGFR) tyrosine kinase
inhibitor (TKI) therapy (Choueiri NEJM 2015/ASCO 2016 abstr 4506),
cabozantinib significantly improved progression-free survival (PFS;
HR 0.58, 95% CI 0.45-0.74; P<0.0001), overall survival (OS; HR
0.66, 95% CI 0.53-0.83, P=0.0003) and objective response rate (ORR;
17% vs 3%; P<0.0001) compared with everolimus.
[0792] Methods: 658 pts were randomized 1:1 to cabozantinib (60 mg
qd) or eve (10 mg qd). Stratification factors were MSKCC risk group
and number of prior VEGFR TKIs. Endpoints included PFS, OS and ORR.
Subgroup analyses by metastatic site and low and high TB
(<median and .gtoreq.median sum of target lesion diameters [SoD]
at baseline) are presented.
[0793] Results: Baseline Characteristics are summarized in Table
3.1. In the overall population represented in Table 3.1, median
target lesion SoD at baseline was 65 mm (range 0-291) in the
cabozantinib arm and 65 mm (range 0-258) in the everolimus arm.
TABLE-US-00027 TABLE 3.1 Baseline Characteristics Patients With Low
Patients With High Tumor Burden Tumor Burden Cabozantinib
Everolimus Cabozantinib Everolimus (N = 165) (N = 163) (N = 165) (N
= 164) Median age, 62 (32-81) 62 (33-81) 63 (36-86) 61 (31-84)
years (range) Male, % 72 69 82 77 Enrollment region, % Europe 47 45
54 49 North America 39 40 33 34 Asia Pacific + 14 15 13 17 Latin
America Median time 2.7 (0-23) 2.6 (0-33) 2.8 (0-30) 2.4 (0-23)
since diagnosis to random- ization, years (range) ECOG performance
status, % 0 73 70 64 62 1 27 30 36 38 MSKCC risk group,.sup.4 %
Favorable 59 56 32 36 Intermediate 37 35 47 47 Poor 4 9 21 17 Tumor
Burden Median 37 (0-65) 41 (0-65) 105 (66-291) 111 (65-258) target
lesion SoD, mm (range) Number of organs with metastatic disease per
IRC, % 1 30 29 5 5 2 30 29 31 18 >3 38 39 64 77 Metastatic sites
per IRC, % Visceral 70 67 76 82 (lung or liver) Lung 59 58 64 71
Liver 21 25 33 38 Lymph node 55 53 70 69 Bone 21 15 26 24 Kidney 14
13 28 27 ECOG, Eastern Cooperative Oncology Group; IRC, independent
radiology committee; MSKCC, Memorial Sloan Kettering Cancer Center;
SoD sum of diameters
[0794] Prior therapies are summarized in Table 3.2PG-5T
TABLE-US-00028 TABLE 3.2 Prior Therapies Patients With Low Tumor
Burden Patients With High Tumor Burden Cabozantinib Everolimus
Cabozantinib Everolimus (N = 165) (N = 163) (N = 165) (N = 164)
Number of VEGFR TKIs, % 1 73 77 69 62 2 or more 27 23 31 38 VEGFR
TKI, % Sunitinib 63 61 64 64 Pazopanib 42 41 45 42 Axitinib 15 10
17 23 Sorafenib 8 8 5 11 Other therapy, % Interleukins 5 7 7 10
Interferons 4 4 7 10 Nivolumab 2 4 8 5 Bevacizumab 1 4 2 2
Radiotherapy 32 33 35 32 Nephrectomy 90 92 82 78 TKI, tyrosine
kinase inhibitor
[0795] FIG. 3.1 depicts progression free survival based on
metastatic site and tumor burden.
[0796] FIG. 3.2 depicts overall survival based on metastatic site
and tumor burden.
[0797] FIG. 3.3 depicts the Kaplan-Meier analysis of overall
survival.
[0798] Table 3.3 summarizes subsequent anticancer therapy.
TABLE-US-00029 TABLE 3.3 Subsequent Anti-Cancer Therapy Patients
With Low Patients With High Tumor Burden Tumor Burden Cabo- Evero-
Cabo- Evero- zantinib limus zantinib limus (N = 165) (N = 163) (N =
165) (N = 164) Systemic 46 59 54 51 therapy, % VEGFR 19 49 28 46
TKI therapies Axitinib 13 33 20 23 Cabozantinib 0 1 0 4 Pazopanib 1
6 2 8 Sorafenib 3 10 2 9 Sunitinib 4 10 7 10 Everolimus 27 6 30 1
Bevacizumab 3 4 2 3 PD-1/PD-L1 3 8 6 3 targeting agents* PD-1,
programmed cell death-1; PD-L1, programmed cell death ligand-1;
TKI, tyrosine kinase inhibitor *The majority (29 out of 33
patients) received nivolumab
[0799] Table 3.4 summarizes the best overall tumor response per
RECIST Version 1.1.
TABLE-US-00030 TABLE 3.4 Best Overall Tumor Response per RECIST
Version 1.1 Patients With Low Patients With High Tumor Burden Tumor
Burden Cabozantinib Everolimus Cabozantinib Everolimus (N = 165) (N
= 163) (N = 165) (N = 164) IRC, % Confirmed 17 (12-24) 7 (3-12) 18
(12-24) 0 ORR.sup.a (95% CI) Stable disease 62 60 68 64 Progressive
disease 16 28 8 26 Investigator assessed, % Confirmed ORR.sup.a, 27
(20-34) 7 (4-13) 21 (15-28) 1 (0-4) % (95% CI).sup.2 Stable disease
59 64 67 62 Progressive disease 10 27 7 27 CI confidence internal,
IRC, independent radiology committee, ORR, objective response rate,
RECIST, Response Evaluation Criteria in Solid Tumors .sup.aAll
responses were partial responses.
[0800] Table 3.5 summarizes all causality Grade 3 or 4 adverse
events.
TABLE-US-00031 TABLE 3.5 All Causality Grade 3 or 4 Adverse
Events.sup.a Patients With Low Patients With High Tumor Burden
Tumor Burden Cabozantinib Everolimus Cabozantinib Everolimus (N =
166) (N = 161) (N = 165) (N = 160) Any, % 73 58 69 62 Hypertension
17 4 12 4 Diarrhea 13 2 13 2 Fatigue 11 7 10 8 PPES 7 1 9 1 Anemia
5 11 7 23 Hyperglycemia 2 4 0 5 PPES palmar-plantar
erythrodysesthesia Syndrome *Events that occurred at a 50%
frequency in either treatment arm in the overall safety population
are summarized. The most common adverse events in patients with
high and low tumor burden were consistent with the safety profile
in the overall population.
[0801] At baseline, 74% of pts had visceral (lung or liver)
metastases (mets); 63% had lung mets and 29% had liver mets. Median
SoD at baseline was 65 mm (range 0-291) in the cabozantinib arm and
65 mm (0-258) in the eve arm. Subgroups by metastatic site and TB
generally had similar baseline characteristics on both arms. High
compared to low TB was associated with fewer favorable (34% vs 57%)
and more intermediate (47% vs 36%) and poor risk (19% vs 7%) pts
per MSKCC criteria. For pts with visceral mets, the HRs favored
cabozantinib (PFS HR 0.48, 95% CI 0.38-0.60; OS HR 0.66, 95% CI
0.52-0.85). These benefits with cabozantinib were consistent across
the metastatic sites analyzed (liver and lung). For pts with low
TB, HRs for cabozantinib vs eve were 0.63 (95% CI 0.47-0.84) for
PFS and 0.76 (95% CI 0.54-1.08) for OS vs 0.41 (95% CI 0.31-0.54)
for PFS and 0.60 (95% CI 0.45-0.80) for OS for pts with high TB.
Median OS with cabozantinib was 22.0 mo for low TB and 18.1 mo for
high TB pts vs 19.3 mo and 12.2 mo with eve, respectively. The most
common grade 3 or 4 adverse events in these subgroups were
consistent with the safety profile in the overall study
population.
[0802] Conclusions: Treatment with cabozantinib was associated with
improved PFS and OS compared to eve in pts irrespective of tumor
burden or metastatic sites. Pts with high tumor burden appeared to
have a stronger relative benefit with cabozantinib compared to eve
for both OS and PFS.
Example 4
Evaluation of the Novel "Trial within a Trial" Design of METEOR, a
Randomized Phase 3 Trial of Cabozantinib Versus Everolimus in
Patients (Pts) with Advanced Renal Cell Carcinoma (RCC)
[0803] Background: Comparative studies of time-to-event endpoints
should be designed to yield a wide range of event times to
accurately characterize the hazard function (HF) relationship and
ensure valid hazard ratio (HR) estimates. The total sample size (N)
is ideally small relative to the required number of events. The
primary endpoint of progression-free survival (PFS) in METEOR
(NCT01865747) required 259 events; the secondary overall survival
(OS) endpoint required 408. As a result, the planned total N (650)
was much larger than required to evaluate PFS. Shorter PFS times
would be overrepresented if an event-driven analysis was conducted
among all 650 pts, potentially undermining the ability to assess
the proportional hazards assumption. To address this, METEOR
employed a novel "trial within a trial" design: PFS was analyzed in
the first 375 randomized pts (PFS Pop); OS was analyzed in all 658
randomized pts (TT Pop). Both populations follow the
intention-to-treat principle.
[0804] Methods: To assess the impact of the design, PFS was
reanalyzed at the date of the 247th event in the ITT Pop (minimum
follow-up [min f/up] 2 days) and compared to both the primary
endpoint results for 247 events in the PFS Pop (min f/up 11 mo) and
supportive results for 394 events in the ITT Pop (min f/up 6
mo).
[0805] Results: FIGS. 4.1-4.4 summarize the findings of Example
4.
[0806] FIG. 4.1 depicts the METEOR trial within a trial statistical
design.
[0807] FIG. 4.2 depicts sample plots from statistical studies. FIG.
4.2A is a simulated study of 260 events among 660 total patients
that demonstrates the potential inability to estimate medians. The
example illustrates the risk that medians cannot be estimated with
a traditional statistical design when the total sample size is
large relative to the number of events required for an endpoint.
The trial within a trial statistical design of limiting the primary
endpoint analysis to the first 375 patients mitigates this
risk.
[0808] FIG. 4.2B demonstrates the potential to mask
non-proportional hazards. Non-proportional hazards arise when the
relative treatment effect is inconsistent over time. In this
condition, a single HR is not an appropriate representation of the
treatment effect. Non-proportional hazards are detected by
non-parallel lines in a log-log plot. This example of a simulated
study of 260 events among 660 total patients illustrates the risk
that the condition of non-proportional hazards may be masked with a
traditional statistical design when the total sample size is large
relative to the number of events required for an endpoint. The
trial within a trial statistical design of limiting the primary
endpoint analysis to the first 375 patients mitigates this
risk.
[0809] The impact of the trial within a trial design on the actual
METOR data, the results of the primary progression free survival
analysis were compared to the results of two alternative analyses.
The results are summarized in Table 4.1.
TABLE-US-00032 TABLE 4.1 Primary and Alternative Progression-Free
Survival Analyses Primary Alternative Analyses PFS Supportive
Traditional Analysis Analysis Analysis TWT All events in
Traditional event- all patients event- driven at time driven
analysis of 1.degree. analysis analysis No. of First 247.sup.a
events All 394 events First 247 events events, among first 375
among all 658.sup.b among all 658 population randomized randomized
randomized Data May 2015 May 2015 Nov 2014 cut-off data Minimum 11
months 6 months 2 days follow-up PFS, progression-free survival;
TWT, trial within a trial .sup.a259 planned events 247 events
included in primary analysis; .sup.b650 planned patients, 658
randomized
[0810] For all analyses: [0811] The proportional hazards assumption
was evaluated using log-log plots [0812] Medians were estimated
using the Kaplan-Meier (KM) method [0813] HRs were estimated using
the Cox proportional hazards model
[0814] Table 4.2 summarizes the hazard ratios and median estimates
in primary and alternative progression free survival analysis.
TABLE-US-00033 TABLE 4.2 Hazard Ratios and Median Estimates in
Primary and Alternative Progression-Free Survival Analyses Analysis
Cut-off Min Median No. of PFS Median, Median, (Population) Date N
Follow-up Follow-up Events HR Cabo Everol Primary TWT May 375.sup.
11 mo 13 mo 247 0.58 7.4 mo 3.8 mo (first 375) 2015 Supportive, all
May 658.sup. 6 mo 11 mo 394 0.51 7.4 mo 3.9 mo events (all 658)
2015 Traditional Nov 656.sup.a 2 days 5 mo 247 0.48 6 mo 3.7 mo
(all 658) 2014 HR, hazard ratio; mo, months; PFS, progression-free
survival; TWT, trial within a trial .sup.aData cut-off before all
subjects are randomized.
[0815] FIG. 4.3 depicts the Kaplan-Meier analysis of progression
free survival.
[0816] FIG. 4.4 depicts the evaluation of proportional hazards
assumption for progression free survival by log-log plots. Lines
are parallel if the proportional hazards assumption is met. For
METOER, the PH assumption generally holds after the first scheduled
tumor assessment approximately 0.68 on x-axis, with a "step
pattern" arising from the periodic nature of tumor assessments. In
all analyses, there is slightly more separation early versus later
in the parallel section, suggestion that a slightly larger
difference between arms among patients with early progression. This
is consistent with the largest relative drop in the KM curve for
the everolimus arm at the first tumor assessment.
[0817] The HFs were reasonably proportional between arms in all
analyses. The HR and median estimate for the cabozantinib arm in
the primary analysis of 247 events in the PFS Pop (0.58, 7.4 mo)
are close to the estimates in the larger analysis of 394 events in
the ITT Pop (0.52, 7.4 mo) using the same cutoff date. Despite the
similar relationship among HFs, an analysis using an earlier cutoff
based upon 247 events in the ITT Pop is biased, overestimating the
treatment benefit as represented by the HR and underestimating the
median PFS in the cabozantinib arm (0.49, 6 mo). A traditional
design would have been biased in terms of overestimating the
treatment benefit as represented by the HR and underestimating the
median PFS in the cabozantinib arm (HR=0.48, median 6 months).
[0818] Conclusions: The "trial within a trial" design provided
critical data required to characterize the HF relationship in
METEOR and demonstrate robust results. This design should be
considered when the HF relationship is unknown and the total N is
large relative to the number of events needed for a time-to-event
endpoint.
Example 5
Analysis of Regional Differences in the Phase 3 METEOR Study of
Cabozantinib (Cabo) Versus Everolimus (Eve) in Advanced Renal Cell
Carcinoma (RCC)
[0819] Background: In the METEOR study (NCT01865747), patients
(pts) with advanced RCC and prior treatment with an antiangiogenic
therapy were randomized to receive cabozantinib or eve. Improved
progression-free survival (PFS), overall survival (OS) and
objective response rate (ORR) were demonstrated in the cabozantinib
arm vs the eve arm (Choueiri 2016 JCO suppl abstr 4506). Baseline
characteristics and clinical outcomes were evaluated in pts
enrolled in three regions: Europe (EU; 19 countries), North America
(NA; US, Canada) and Asia Pacific (AP; Australia, South Korea,
Taiwan).
[0820] Methods: 658 pts were randomized 1:1 to receive cabozantinib
(60 mg qd) or eve (10 mg qd). Stratification factors were MSKCC
risk group and number of prior vascular endothelial growth factor
receptor (VEGFR) tyrosine kinase inhibitors (TKIs).
[0821] Results: Table 5.1 summarizes the baseline characteristics
of the enrolled patients.
TABLE-US-00034 TABLE 5.1 Baseline Characteristics Europe North
America Asia Pacific Caboz- Evero- Caboz- Evero- Caboz- Evero-
antinib limus antinib limus antinib limus (N = 167) (N = 153) (N =
118) (N = 122) (N = 39) (N = 47) Median age, 63.0 63.0 63.0 61.5
59.0 60.0 years (range) (32-86) (33-84) (36-83) (37-84) (38-78)
(31-81) Male, % 73 75 81 79 82 55 Median time from 3.0 2.6 2.8 2.7
2.1 2.3 diagnosis to (0-30) (0-19) (0-20) (0-33) (0-23) (0-16)
randomization, years (range) ECOG performance status, % 0 66 68 68
62 77 64 1 34 32 32 38 23 36 MSKCC risk group, % Favorable 47 48 42
40 41 51 Intermediate 38 37 47 49 49 36 Poor 15 15 10 11 10 13
Race, % White 83 80 89 91 49 51 Asian 1 1 2 3 46 45 Black 0 0 5 2 0
0 Other 8 7 3 2 5 2 Not reported 8 13 1 2 0 2 Metastatic sites per
IRC, % Lung 62 65 56 61 74 72 Liver 25 37 31 26 26 30 Bone 22 22 27
19 21 15 ECOG, Eastern Cooperative Oncology Group; IRC, independent
radiology committee; MSKCC, Memorial Sloan Kettering Cancer
Center
[0822] FIG. 5.1 depicts the METEOR enrollment in countries as a
percentage of total enrolled patients.
[0823] Table 5.2 summarizes prior therapies.
TABLE-US-00035 TABLE 5.2 Baseline Prior Therapies Europe North
America Asia Pacific Caboz- Evero- Caboz- Evero- Caboz- Evero-
antinib limus antinib limus antinib limus (N = 167) (N = 153) (N =
118) (N = 122) (N = 39) (N = 47) Number of VEGFR TKIs, % 1 68 71 70
64 85 81 2 29 28 25 31 15 19 3 or more 2 1 6 5 0 0 VEGFR TKI, %
Sunitinib 71 66 58 60 62 64 Pazopanib 35 35 51 47 49 43 Axitinib 16
18 22 21 0 2 Sorafenib 8 8 4 11 5 11 Other therapy, % Interleukins
5 6 9 16 0 2 Interferons 10 14 2 2 0 2 Anti-PD-1/PD-L1 4 4 9 6 3 2
Bevacizumab 1 5 3 3 0 2 Radiotherapy 31 29 39 40 31 26 Nephrectomy
84 86 88 86 85 81 PD-1, programmed cell death-1; PD-L1, programmed
cell death ligand-1; TKI, tyrosine kinase inhibitor
[0824] FIG. 5.2 provides Forest plots of progression free survival
per IRC by Region.
[0825] FIG. 5.3 provides Forest plots of overall survival per IRC
by Region.
[0826] Table 5.3 summarizes the best overall tumor response per
RECIST Version 1.1 by region.
TABLE-US-00036 TABLE 5.3 Best Overall Tumor Response per RECIST
Version 1.1 by Region.sup.a Europe North America Asia Pacific
Cabozantinib Everolimus Cabozantinib Everolimus Cabozantinib
Everolimus (N = 167) (N = 153) (N = 118) (N = 122) (N = 39) (N =
47) IRC, % ORR.sup.b 15 4 16 2 28 2 (95% CI) (10-21) (1-8) (10-24)
(1-7) (15-45) (0-11) Stable disease 69 65 62 59 62 60 Progressive
disease 10 24 17 30 10 28 Investigator assessed, % ORR.sup.b 22 4
20 3 36 4 (95% CI) (16-29) (1-8) (13-29) (1-8) (21-53) (1-15)
Stable disease 65 66 62 62 64 60 Progressive disease 8 25 13 29 0
26 CI, confidence interval; IRC, independent radiology committee;
ORR, objective response rate; RECIST, Response Evaluation Criteria
in Solid Tumors .sup.aThe sum of responses is less than 100%
because there were patients with not evaluable or missing
assessments in both arms. .sup.bAll responses were confirmed
partial responses.
[0827] Table 5.4 summarizes subsequent anticancer therapy.
TABLE-US-00037 TABLE 5.4 Subsequent Anti-Cancer Therapy Europe
North America Asia Pacific Subsequent Cabozantinib Everolimus
Cabozantinib Everolimus Cabozantinib Everolimus Therapy (N = 167)
(N = 153) (N = 118) (N = 122) (N = 39) (N = 47) Any systemic anti-
50 55 53 66 44 34 cancer therapy, % Any VEGFR 25 50 29 57 5 21 TKI
Axitinib 17 28 22 38 3 2 Sorafenib 4 14 3 6 0 6 Sunitinib 4 11 8 9
3 11 Pazopanib 2 8 2 7 0 4 Cabozantinib 0 1 0 6 0 0 Everolimus 30 4
28 4 33 9 Anti-PD-1/PD-L1 2 2 9 13 3 0 PD-1, programmed cell
death-1; PD-L1, programmed cell death ligand-1; TKI, tyrosine
kinase inhibitor
[0828] Table 5.5 summarizes study treatment exposure and dose
reductions.
TABLE-US-00038 TABLE 5.5 Study Treatment Exposure and Dose
Reductions Europe North America Asia Pacific Cabozantinib
Everolimus Cabozantinib Everolimus Cabozantinib Everolimus (N =
167) (N = 153) (N = 118) (N = 122) (N = 39) (N = 47) Median
duration of 33 21 39 16 56 24 exposure, wks Patients receiving 62
27 58 26 72 13 dose reductions, % Median average 43.6 9.1 43.3 8.7
41.0 9.4 daily dose, mg Median time to 55 64 59 64 57 51 first dose
reduction, days Wks, weeks
[0829] Table 5.6 summarizes all causality Grade 3 or 4 adverse
events.
TABLE-US-00039 TABLE 5.6 All Causality Grade 3 or 4 Adverse
Events.sup.a Europe North America Asia Pacific Cabozantinib
Everolimus Cabozantinib Everolimus Cabozantinib Everolimus (N =
167) (N = 153) (N = 118) (N = 122) (N = 39) (N = 47) Any, %
Hypertension 17 7 14 1 5 2 Diarrhea 13 2 14 2 10 4 Fatigue 11 6 13
10 5 4 PPES 9 1 7 1 8 0 Anemia 5 17 7 13 5 26 Hyperglycemia 1 1 2
10 0 4 AE, adverse event; PPES, palmar-plantar erythrodysesthesia
syndrome .sup.aAEs that occurred at .gtoreq. 5.0% frequency in
either treatment arm of the overall safety population are
summarized.
[0830] Of pts enrolled in METEOR, 320, 240 and 86 came from EU, NA
and AP, respectively. Baseline demographic characteristics other
than race were similar between regions. Pts with 2 or more prior
TKIs were more frequent in EU and NA (31% and 33%) than AP (17%).
Prior use of axitinib was rare in AP (1%) compared to EU and NA
(17% and 22%). PFS and OS in the cabozantinib arm were prolonged vs
eve in all regions, with PFS hazard ratios (HR) of 0.54, 0.50 and
0.43 and OS HRs of 0.67, 0.79 and 0.49 for EU, NA and AP,
respectively. The cabozantinib arm ORRs (% [95% CI]) for EU, NA and
AP regions were 15% (10-21), 16% (10-24) and 28% (15-45). Adverse
event (AE) rates were generally similar across regions. Subsequent
treatment with VEGFR-TKI and anti-PD-1/L1 agents was most frequent
in NA and least frequent in AP, and at higher frequency in the eve
arm versus the cabozantinib arm. Post trial use of eve in the
cabozantinib arm was similar across regions.
[0831] Conclusions: Improvements in PFS, OS and ORR for
cabozantinib vs eve were measured across all regions in the METEOR
trial despite differences in subsequent treatment. No differences
in safety were reported.
Example 6
Clinical Outcomes for Canadian Patients in the Phase 3 METEOR Study
of Cabozantinib (Cabo) Versus Everolimus (Eve) in Advanced Renal
Cell Carcinoma (RCC)
[0832] Background: In the METEOR study (NCT01865747), patients
(pts) with advanced RCC and prior treatment with vascular
endothelial growth factor receptor (VEGFR) tyrosine kinase
inhibitor (TKI) therapy were randomized to receive cabo or eve.
Cabo demonstrated improved progression-free survival (PFS) (median
7.4 vs 3.8 mo; HR 0.58, 95% CI 0.45-0.74; P<0.0001), overall
survival (OS) (median 21.4 vs 16.5 mo; HR 0.66, 95% CI 0.53-0.83,
P=0.0003), and objective response rate (ORR) (17% vs 3%;
P<0.0001) compared with eve (Choueiri NEJM 2015, Lancet Oncol
2016). Here we evaluate clinical outcomes for patients enrolled in
Canada.
[0833] Methods: 658 pts were randomized 1:1 to receive cabo (60 mg
qd) or eve (10 mg qd) with stratification by MSKCC risk group and
number of prior VEGFR TKI therapies.
[0834] Results: Forty pts were enrolled at 1:1 sites in Canada, 23
pts in the cabo arm and 17 pts in the eve arm. Median PFS was 7.4
mo (95% CI, 4.3-NE) with cabo and 3.7 mo (95% CI, 1.7-4.7) with eve
(HR 0.40; 95% CI, 0.17-0.89). Median OS was 20.8 mo (95% CI,
13.1-NE) with cabo and 12.8 mo (95% CI, 5.5-15.9) with eve (HR
0.33; 95% CI, 0.14-0.75). ORR for the cabo arm was 17% (95% CI,
0.14-0.75) vs 0% for the eve arm. The median duration of exposure
was 9.2 mo with cabo and 3.7 mo with eve. The proportion of pts who
received subsequent systemic anticancer therapy was 39% in the cabo
arm vs 59% in the eve arm.
[0835] Conclusions: These results from Canadian patients with
advanced RCC enrolled in METEOR are consistent with the overall
study population, with observed improvements with cabo compared to
eve in the 3 key efficacy endpoints of PFS, OS, and ORR.
Example 7
Overall Survival (OS) and Subgroup Analysis Results from ALLIANCE
A031203 Trial: Cabozantinib Versus Sunitinib (CABOSUN) as Initial
Targeted Therapy for Patients (Pts) with Metastatic Renal Cell
Carcinoma (mRCC)
[0836] Background: Cabozantinib (Cabo) is an oral, potent inhibitor
of MET, AXL and VEGFR2 that increases progression free-survival
(PFS) and overall response rate (ORR) compared to Sunitinib (Sun)
as front-line targeted therapy in patients (pts) with mRCC of poor
or intermediate risk (Choueiri et al, JCO 2016). Overall survival
(OS) results will be presented.
[0837] Methods: Eligible pts had untreated clear-cell mRCC, ECOG
performance status 0-2, and intermediate or poor risk disease, per
the International mRCC Database Consortium Criteria (IMDC, Heng J C
O 2009). Pts were randomized 1:1 to receive Cabo (60 mg QD) or Sun
(50 mg QD, 4 weeks on/2 weeks off). Pts were stratified by the IMDC
risk groups (intermediate vs. poor risk) and bone metastasis (yes,
no). The primary endpoint was PFS. With 123 events, the log-rank
statistic has 85% power to detect a hazard ratio of 0.67 for PFS
assuming a one-sided type I error of 0.12. Secondary endpoints
included OS, investigator-assessed overall response rate (ORR), and
toxicity. The Kaplan-Meier product-limit estimator was used to
estimate the OS between treatment arms.
[0838] Results: See previous Examples, including Examples 1, 3, and
5 and Example 9. Compared with sunitinib, cabozantinib treatment
significantly increased median PFS (8.2 v 5.6 months) and was
associated with a 34% reduction in rate of progression or death
(adjusted hazard ratio, 0.66; 95% CI, 0.46 to 0.95; one-sided
P=0.012). ORR was 46% (95% CI, 34 to 57) for cabozantinib versus
18% (95% CI, 10 to 28) for sunitinib. All-causality grade 3 or 4
adverse events were 67% for cabozantinib and 68% for sunitinib and
included diarrhea (cabozantinib, 10% v sunitinib, 11%), fatigue (6%
v 15%), hypertension (28% v 22%), palmar-plantar erythrodysesthesia
(8% v 4%), and hematologic adverse events (3% v 22%). Median OS
with cabozantinib was 30.3 months (95% CI, 14.6 to 35.0 months)
versus 21.8 months (95% CI, 16.3 to 27.0 months) with sunitinib
(adjusted HR, 0.80; 95% CI, 0.50 to 1.26.
Example 8
Efficacy of Cabozantinib (C) Vs Everolimus (E) in Patients with
Advanced Renal Cell Carcinoma (RCC) and Bone Metastases from the
Phase 3 METEOR Study
[0839] In patients with metastatic RCC, bone metastases are
prognostic for poor outcomes and represent an unmet medical need.
The Phase 3 METEOR trial (NCT01865747) assessed the efficacy and
safety of cabozantinib vs everolimus in patients with RCC and
.gtoreq.1 prior VEGFR TKI. The trial met its primary endpoint of
improving progression-free survival (PFS; HR 0.58, 95% CI
0.45-0.75; P<0.001) (Chouciri NEJM 2015). As cabozantinib has
shown clinical activity in bone metastases in prostate cancer
patients (Smith J C O 33 2015 abs 139), we evaluated clinical
outcomes in RCC patients with bone metastases in METEOR.
[0840] In the METEOR Phase 3 study, treatment with cabozantinib
resulted in statistically significant improvements in
progression-free survival (PFS), overall survival (OS), and
objective response rate (ORR) compared with everolimus in advanced
RCC patients. FIG. 8.1 depicts the progression-free survival per
independent radiology committee (IRC) in all 658 randomized
patients. FIG. 8.2 depicts the overall survival over 30 months.
[0841] Methods: 658 patients were randomized (stratified by MSKCC
risk group and number of prior VEGFR TKIs) 1:1 to receive
cabozantinib (60 mg qd) or everolimus (10 mg qd). The study design
in depicted in FIG. 8.3. Clinical outcome measures included PFS,
ORR, overall survival (OS), and safety. Exploratory endpoints
included bone scan response (BSR) in patients with bone scan
lesions at baseline (Brown Nucl Med Commun 2012 33:384), incidence
of skeletal-related events (SRE), and changes in bone turnover
markers.
[0842] Table 8.1 depicts the baseline characteristics of the
patients. The subgroup of patients with bone metastases (N=142) was
defined by the presence of bone metastases at baseline by CT or MRI
per IRC. Bone scan response (BSR) was evaluated for patients who
had bone lesions detected by technetium bone scans at baseline
(N=178).
TABLE-US-00040 TABLE 8.1 Baseline Characteristics Pts with Bone
Metastases.sup.1 Pts without Bone Metastases Cabozantinib
Everolimus Cabozantinib Everolimus (N = 77) (N = 65) (N = 253) (N =
263) Median age, years (range) 61.0 (32-84) 64.0 (34-84) 63.0
(35-86) 61.0 (31-81) Male, % 83 82 75 71 Enrollment Region, %
Europe 47 52 52 45 North America 42 35 34 38 Asian Pacific + Latin
American 11 13 14 17 ECOG Performance Status, % 0 83 92 94 94 1 17
8 6 6 MSKCC risk group.sup.1, % Favorable 36 45 48 46 Intermediate
45 42 41 41 Poor 18 14 11 13 Visceral metastases per IRC, % 78 80
72 73 .sup.122% (142/658) of randomized patients had bone
metastases by CT or MRI at baseline. 2. Motzer R. et al, J Clin
Oncol, 2004
[0843] The prior therapies for both patients with bone metastases
and without bone metastases am shown in Table 8.2. The concomitant
use of bone-targeted therapies in patients with bone metastases at
baseline is shown in Table 8.3. Table 8.3 includes patients who
initiated bone-targeted therapy prior to randomization.
TABLE-US-00041 TABLE 8.2 Prior Therapies Pts with Bone Metastases
Pts without Bone Metastases Cabozantinib Everolimus Cabozantanib
Everolimus (N = 77) (N = 65) (N = 253) (N = 263) Number of VEGFR
TKIs, % 1 65 66 73 71 2 or more 35 24 27 29 VEGFR-TKI, % Sunitinib
61 59 64 64 Pazopanib 46 48 43 40 Axitinib 22 23 14 15 Sorafenib 7
11 6 9 Other systemic therapy, % Interleukins 8 5 6 10 Interferon
alfa 4 9 6 6 Nivolumab 5 6 5 4 Bevacizumab 3 6 1 3 Radiotherapy, %
56 62 27 26 Nephrectomy, % 87 72 85 88
TABLE-US-00042 TABLE 8.3 Concomitant use of Bone-Targeted Therapies
in Patients with Bone Metastases at Baseline Cabozantinib
Everolimus (n = 77) (n = 65) Bone-targeted therapy at baseline, n
(%) Bisphosphonate 18 11 Denosumab 12 9 Bone-targeted therapy
post-randomization,* n (%) Bisphosphonate 23 20 Denosumab 13 12
[0844] Assessments: Participants were screened via CT or MRI every
8 weeks for the first 12-months post-randomization, and then every
12 weeks thereafter. Technetium bone scans were performed at
screening (all patients), every 16 weeks for the first 12 months
post-randomization (only in patients with bone lesions at
baseline), and then every 23 weeks thereafter. Skeletal-related
events (SREs) were assessed and consisted of pathological
fractures, spinal cord compression, surgery to bone, and external
radiation therapy to bone.
[0845] Serum bone marker analyses consisted on N-terminal
propeptide of type I collagen (PINP), and the bone resorption
marker c-terminal cross-lined telopeptides of type I collagen
(CTx), which were collected prior to the first dose at week 1, at
week 5, and at week 9.
[0846] Results: 142 patients had bone metastases at baseline; of
these, 112 had visceral metastases also. MSKCC risk groups in
patients with bone metastases were consistent with the overall
study population. PFS HRs of cabozantinib vs everolimus were 0.33
(bone; 95% CI 0.21-0.51) and 0.26 (bone+visceral; 95% CI
0.16-0.43). Median PFS with cabozantinib was 7.4 mo in patients
with bone metastases and 5.6 mo in patients with bone and visceral
metastases compared to 2.7 mo and 1.9 mo with everolimus
respectively. The ORR with cabozantinib was 17% and 20%,
respectively. BSR by IRC was 18% (cabozantinib) vs 10%
(everolimus). 12% (cahozantinib) and 14% (everolimus) of randomized
patients had at least one SRE, including 4 (cabozantinib) and 8
(everolimus) cases of spinal cord compression. For patients with an
SRE pre-randomization, the incidence of post-randomization SREs was
16% (cabozantinib) and 34% (everolimus) and included 0
(cabozantinib) and 5 (everolimus) cases of spinal cord compression
(Tables 8.4 and 8.6). Reductions in bone markers were greater with
cabozantinib vs everolimus (Table 8.9). The most common adverse
events (AE) in patients with bone metastases were consistent with
the safety profile in the overall study population (Table 8.6).
TABLE-US-00043 TABLE 8.4 Post-Randomization Skeletal-Relates Events
(SREs) Pts with Bone Metastases Pts without Bone Metastases
Cabozantinib Everolimus Cabozantinib Everolimus N = 77 N = 65 N =
253 N = 263 Post- 16 (21) 19 (29) 22 (9) 27 (10) Randomization
SREs, n (%) Pathologic 9 (12) 3 (5) 7 (3) 8 (3) fractures Spinal
cord 2 (3) 4 (6) 2 (1) 4 (2) compression Surgery to bone 6 (8) 5
(8) 5 (2) 5 (2) External 7 (9) 16 (25) 18 (7) 19 (7) radiation
therapy to bone Time to first 3.45 2.53 3.93 4.27 SRE, median
(0.4-10.5) (0.3-7.3) (0.5-11.3) (0.7-13.4) (95% CI), months
TABLE-US-00044 TABLE 8.5 Post-Randomization Skeletal-Related Events
(SREs) in Patients with a Prior History of SREs Patients with a
prior history of SREs Pts With Bone Metastases Pts without Bone
Metastases Cabozantinib Everolimus Cabozantinib Everolimus N = 43 N
= 43 N = 48 N = 47 SREs in 10 (2) 14 (33) 5 (10) 17 (36) patients
with a prior history of SREs, n (%) Pathologic 6 (14) 2 (5) 3 (6) 6
(13) fractures Spinal cord 0 2 (5) 0 3 (6) compression Surgery to
bone 4 (9) 3 (7) 2 (4) 4 (9) External 4 (9) 12 (28) 4 (8) 11 (23)
radiation therapy to bone Time to first 3.25 2.41 2.76 4.27 SRE,
median (0.4-10.5) (0.3-7.3) (0.7-7.6) (0.7-11.5) (95% CI),
months
TABLE-US-00045 TABLE 8.6 All Casualty Grade 3 or 4 Adverse Events
Pts with Bone Metastases Pts without Bone Metastases Cabozantinib
Everolimus Cabozantinib Everolimus N = 77 N = 65 N = 254 N = 257
Any, n (%) 52 (68) 32 (49) 174 (69) 154 (60) Fatigue 10 (13) 3 (5)
20 (8) 19 (7) Diarrhea 9 (12) 0 29 (11) 7 (3) PPES 6 (8) 0 21 (8) 3
(1) Hypertension 5 (6) 1 (2) 44 (17) 9 (4) Anemia 4 (5) 9 (14) 14
(6) 41 (16) Hypomagnesaemia 3 (4) 0 12 (5) 0 Hyperglycemia 0 5 (8)
2 (1) 11 (4) Hypokalaemia 4 (5) 1 (2) 11 (4) 5 (2) Event of
interest Hypercalcemia 0 2 (3) 2 (1) 4 (2) Events that occurred at
.gtoreq. 5% frequency in either treatment arm in the overall safety
population and the incidence of grade 3 or 4 hypercalcemia are
summarized. The most common AEs in pts with and without bone
metastases were consistent with the safety profile in the overall
population. Grade 5 (related) AEs in pts with bone metsatases:
everolimus (n = 1; pneumonia aspiration). Grade 5 (related) AEs in
pts without bone metsatases: cabozantinib (n = 1; death not
otherwise specified); everolimus (n = 1; infection ). indicates
data missing or illegible when filed
[0847] The objective response rates are outlined in Table 8.7.
TABLE-US-00046 TABLE 8.7 Objective Response Rate per RECIST version
1.1 Pts with Bone and Pts with Bone Metastases Visceral.sup.1
Metastases Pts without Bone Metastases Cabozantinib Everolimus
Cabozantinib Everolimus Cabozantinib Everolimus n = 77 n = 65 n =
60 n = 52 n = 253 n = 263 IRC Confirmed responses, 17 (9-27) 0 20
(11-32) 0 17 (13-23) 4 (2-7) % (95% Cl).sup.3 Stable disease, (%)
70 54 65 44 64 64 Progressive disease, (%) 13 37 15 44 12 24
Investigator assessed Confirmed responses, 27 (18-39) 0 30 (19-43)
0 23 (18-28) 5 (3-9) % (95% Cl).sup.3 Stable disease, (%) 64 63 60
59 63 63 Progressive disease, 9 26 10 29 9 26 (%) .sup.1Visceral
metastases were defined as lung or liver metastases. .sup.3All
responses were partial responses.
[0848] FIG. 8.4 shows Kaplan-Meier analyses of progression-free
survival in patients with bone metastases, patients with bone and
visceral metastases, and patients without bone metastases. FIG. 8.5
shows Kaplan-Meier analyses of overall survival in patients with
bone metastases, patients with bone and visceral metastases, and
patients without bone metastases.
[0849] Bone scan responses per IRC in patients with bone scan
lesions were performed using computer-assisted detection of bone
scan lesions. An IRC was used to quantitate bone scan tumor burden
using computer-assisted detection (CAD) to measure lesions and
defined criteria for response. Bone scan lesion area (BSLA), which
represents the number of pixels with radiotracer uptake above the
threshold for normal bone, was also calculated. BSR was defined as
greater than or equal to 30% decrease in BSLA. The bone scan
response is shown in Table 8.8.
TABLE-US-00047 TABLE 8.8 Bone Scan Response per IRC in Patients
with Bone Scan Lesions Pts with bone lesions at baseline by bone
scan Cabozantinib Everolimus N = 105 N = 73 Bone scan response, 18
(11, 27) 10 (4, 19) % (95% CI)
[0850] FIG. 8.6 and Table 8.9 depict the effect of cabozantinib on
bone markers for patients with bone metastases at baseline. FIG.
8.7 depicts the effect of cabozantinib on bone markers for patients
without bone metastases at baseline.
TABLE-US-00048 TABLE 8.9 Cabozantinib Everolimus Baseline* Week 5*
Baseline* Week5* N-terminal 48.5 38.9 49.9 44.1 propeptide of type
1 collagen (P1NP) C-terminal 0.40 0.19 0.43 0.43 cross-lined
telopeptides of type 1 collagen (CTx) *Median, ug/L
[0851] Conclusions: Treatment with cabozantinib was associated with
improved PFS, OS, and ORR in patients with or without bone
metastases as compared to everolimus. This clinical benefit was
supported by the outcomes of bone metastasis-related endpoints.
Example 9
Outcomes Based On Prior VEGF TKI and PD-1 Checkpoint Inhibitor
Therapy in METEOR, a Randomized Phase 3 Tiral of Cabozantinib vs
Everolimus in Advanced Renal Cell Carcinoma
[0852] Background Optimizing the sequence of systemic therapy to
improve outcomes in patients with advanced renal cell carcinoma
(RCC) remains a clinical question. Cabozantinib, a tyrosine kinase
inhibitor (TKI), was recently evaluated in patients with RCC and
.gtoreq.1 prior vascular endothelial growth factor receptor (VEGFR)
TKI therapies in the Phase 3 METEOR trial (NCT01865747) (FIG. 4).
658 patients were randomized 1:1 to receive cabozantinib (60 mg
once daily [qd]) or everolimus (10 mg qd). Stratification was by
Memorial Sloan Kettering Cancer Center (MSKCC) risk group
(favorable, intermediate, poor) and number of prior VEGFR TKIs (1,
.gtoreq.2)
[0853] Eligibility criteria included: RCC with clear cell
component; Prior treatment with at least 1 VEGFR TKI; Radiographic
progression during treatment or within 6 months after most recent
TKI regimen; Prior treatment with anti-PD-1/PD-L1 agents was
allowed.
[0854] Progression-free survival (PFS) by independent radiology
committee (IRC), overall survival (OS), and objective response rate
(ORR) by IRC were significantly improved compared with everolimus
(FIGS. 3 and 4), providing a Median PFS of 7.4 vs 3.9 months,
HR=0.51, 95% CI: 0.41-0.62; P<0.0001; a Median OS of 21.4 vs
16.5 months, HR=0.66, 95% CI: 0.53-0.83; P=0.0003; and an ORR of
17% for cabozantinib vs 3% for everolimus (P<0.0001)
[0855] The goal of this study was to better understand efficacy
outcomes by prior VEGFR TKI.
[0856] Methods. Demographics, efficacy, and safety endpoints were
evaluated in subgroups defined by prior anticancer therapy. [0857]
Sunitinib only: patients with sunitinib as the only prior VEGFR TKI
therapy [0858] Pazopanib only: patients with pazopanib as the only
prior VEGFR TKI therapy [0859] Anti-PD-1/PD-L1: patients with prior
exposure to immune checkpoint inhibitors targeting PD-1 or
PD-L1
[0860] Clinical outcome measures included PFS (primary endpoint),
OS, ORR, and safety. Tumor assessment was by IRC and utilized
Response Evaluation Criteria in Solid Tumors, (RECIST) v1.1.
Adverse events were reported according to National Cancer Institute
Common Terminology Criteria for Adverse Events, v4.0
[0861] Data cut-off: All data are as of May 22, 2015 except for the
OS analyses which are as of Dec. 31, 2015.
[0862] The prior therapy subgroups and baseline characteristics are
summarized in Tables 9.1 and 9.2.
TABLE-US-00049 TABLE 9.1 Prior Therapy Subgroups Prior Anticancer
Cabozantinib Everolimus Regimens, n(%) (N = 330) (N = 328) 1 prior
VEGFR TKI 235 (71) 229 (70) Sunitinib only 135 (41) 132 (440)
Pazopanib only 88 (27) 83 (25) .gtoreq.2 prior VEGFR TKI 95 (29) 99
(30) Anti-PD-1/PD-L1* 18 (5) 14 (4) *31 patients received
nivolumab, 1 patient received atezolizumab
TABLE-US-00050 TABLE 9.2 Baseline Characteristics Sunitinib Only
Pazopanib Only Anti-PD-1/PD-L1 Cabozantinib Everolimus Cabozantinib
Everolimus Cabozantinib Everolimus N = 135 N = 132 N = 88 N = 83 N
= 18 N = 14 Median age, years 62.0 62.0 63.0 61.0 63.5 61.0 (range)
(37-79) (31-81) (38-86) (36-84) (47-81) (37-84) Male, % 79 72 77 77
72 79 Enrollment region, % Europe 53 50 39 41 33 43 North America
33 33 40 39 61 50 Asia Pacific 13 17 15 16 6 7 Latin America 0 1 7
5 0 0 ECOG Performance Status*, % 0 70 66 75 59 67 64 1 30 34 25 41
33 36 MSKCC risk group.sup.4, % Favorable 41 45 45 42 28 43
Intermediate 47 44 44 45 50 50 Poor 13 11 10 13 22 7 Metastatic
sites per IRC, % Lung 59 67 70 65 56 79 Liver 32 42 25 19 33 29
Bone 20 17 23 22 28 29 Prior Therapy VEGFR TKI, % Sunitinib 100 100
-- -- 67 64 Pazopanib -- -- 100 100 61 43 Axitinib -- -- -- -- 28
21 Sorafenib -- -- -- -- 6 14 Other therapy, % Interleukins 5 5 5 8
11 0 Interferon-alfa 3 5 7 6 6 0 Nivolumab 4 4 1 4 94 100
Bevacizumab 0 2 1 4 6 7 Radiotherapy 29 31 40 31 33 36 Nephrectomy
86 85 86 78 89 79 *Based on Karnofsky Performance Status score
[0863] Results. The results are summarized in FIGS. 9.1-9.5 and
Tables 9.3 and 9.4.
[0864] FIG. 9.1 depicts the progression free survival of subgroups
based on prior therapy (sunitibib, pazopanib, or
Anti-PD-1/PD-L1).
[0865] FIG. 9.2 depicts the Forest Plot analysis of overall
survival.
[0866] FIG. 9.3 depicts the overall survival of subgroups based on
prior therapy (sunitibib, pazopanib, or Anti-PD-1/PD-L1).
[0867] FIG. 9.4 depicts the analysis of progression free
survival.
[0868] Table 9.3 summarizes the objective response rate among prior
therapy subgroups.
TABLE-US-00051 TABLE 9.3 Sunitinib Only Pazopanib Only
Anti-PD-1/PD-L1 Cabo- Evero- Cabo- Evero- Cabo- Evero- zantinib
limus zantinib limus zantinib limus N = 135 N = 132 N = 88 N = 83 N
= 18 N = 14 Tumor response by IRC (%) Confirmed ORR* 16 3 19 4 22 0
(95% CI) (11-24) (1-8) (12-29) (1-10) (6-48) Stable disease 66 57
65 66 50 64 Progressive disease 12 35 14 22 11 29 Tumor response by
investigator (%) Confirmed ORR* 23 4 31 4 22 0 (95% CI) (16-31)
(1-9) (21-41) (1-10) (6-48) Stable disease 60 63 64 64 56 86
Progressive disease 11 29 3 27 11 14 *All partial responses
[0869] FIG. 9.5 depicts the progression free survival and response
in Anti-PD-1/PD-L1 subgroup.
[0870] Table 9.4 summarizes grade 3 and 4 adverse events per prior
therapy.
TABLE-US-00052 TABLE 9.4 Sunitinib Only Pazopanib Only
Anti-PD-1/PD-L1 Cabozantinib Everolimus Cabozantinib Everolimus
Cabozantinib Everolimus N = 135 N = 132 N = 88 N = 83 N = 18 N = 14
Any, n (%) 86 (64) 77 (59) 62 (70) 50 (62) 15 (83) 8 (57)
Hypertension 22 (16) 5 (4) 14 (16) 1 (1) 4 (22) 0 Diarrhea 19 (14)
4 (3) 8 (9) 0 2 (11) 0 Fatigue 14 (10) 8 (6) 3 (3) 8 (10) 5 (28) 2
(14) Palmar-plantar 11 (8) 0 9 (10) 2 (2) 3 (17) 1 (7)
erythrodysesthesia Anemia 11 (8) 22 (17) 2 (2) 7 (9) 2 (11) 2 (14)
Hypomagnesemia 8 (6) 0 3 (3) 0 0 0 Hypokalemia 7 (5) 2 (2) 2 (2) 3
(4) 1 (6) 0 Hyperglycemia 0 6 (5) 1 (1) 3 (4) 0 0 *Events that
occurred at > 5% frequency in either treatment arm in the
overall safety population
[0871] Conclusion. Efficacy outcomes by prior VEGFR TKI therapy
consistently favored cabozantinib over everolimus. The Median PFS
in the cabozantinib arm was 9.1 months for sunitinib only and 7.4
months for pazopanib only. The Median OS in the cabozantinib arm
was 21.4 months for sunitinib only and 22.0 months for pazopanib
only. The prior anti-PD-1/PD-L1 subgroup was small. However,
preliminary data suggest that the clinical benefit of cabozantinib
is maintained in these patients as well. Adverse events in
subgroups were similar to the overall study population.
[0872] We therefore conclude that cabozantinib is a new standard of
care for patients with advanced RCC after prior anti-angiogenic
therapy.
Example 10
Population Pharmacokinetic (PopPK) and Exposure-Response (ER)
Modeling of Cabozantinib (C) in Patients (Pts) with Renal Cell
Carcinoma (RCC) in the Phase 3 METEOR Study
[0873] Population pharmacokinetic (PopPK) and exposure-response
(ER) modeling of cabozantinib (C) in patients (pts) with renal cell
carcinoma (RCC) in the phase 3 METEOR study
[0874] Summary PopPK and ER models were developed to characterize
the C concentration-time profile and the relationship between C
exposure and efficacy endpoints in patients with RCC.
[0875] Background Cabozantinib is a tyrosine kinase inhibitor (TKI)
which targets VEGF receptors, MET, and AXL. In the phase 3 METEOR
trial, cabozantinib treatment significantly improved
progression-free survival (PFS), overall response rate (ORR) and
overall survival (OS) compared to everolimus in patients with
advanced renal cell carcinoma (RCC) who had received prior VEGFR
inhibitor therapy. Because of variability in pharmacokinetics (PK)
of TKIs such as cabozantinib, drug concentrations/exposure can vary
from patient to patient despite treatment at the same dose. In the
METEOR study, all patients started at a daily cabozantinib tablet
dose of 60 mg, but could dose reduce to 40 mg or 20 mg to achieve a
tolerated exposure as specified in the protocol. Dose
reductions/modifications are frequently used with TKIs to manage
adverse events (AEs) and individualize treatment.
[0876] To better understand factors affecting cabozantinib PK
variability in RCC patients, a population pharmacokinetic (PopPK)
model was developed to characterize the cabozantinib
concentration-time profile and to identify statistically
significant covariates for cabozantinib clearance.
[0877] To better understand the impact of cabozantinib exposure on
efficacy in RCC patients, exposure-response (ER) models were
developed to characterize the relationship between cabozantinib
exposure and efficacy endpoints (PFS, tumor regression) at plasma
concentrations associated with the cabozantinib doses that patients
received in the METEOR study (60 mg, 40 mg, 20 mg qd).
[0878] Methods. The PopPK model was developed using nonlinear mixed
effects modeling methodology (NONMEM v7.3;) that incorporated 1650
measurable PK concentrations from 345 subjects (Table 10.1).
TABLE-US-00053 TABLE 10.1 Study Cabozantinib Tumor Diameter Number
Phase Description Treatment.sup.a Population PK Samples
Measurements.sup.b XL184-020 1 Pharmacokinetic study Single dose po
Healthy subjects Pre-dose and 0.5, NA in healthy adult (20, 40 or
60 mg) (63 subjects) 1, 2, 3, 4, 5, 6, 8, subjects 10, 14, 24, 48,
72, 120, 168, 240, 288, 336, 408, and 504 hours post- dose
XL184-308 3 Cabozantinib vs 60 mg po qd RCC Patients One sample~8
or Screening and every 8 (METEOR) Everolimus in patients (dose
reductions to (approximately more hours after weeks for the first
12 with advanced RCC 40 or 20 mg qd 325 cabozantinib the prior
evening months, and every 12 who had progressed allowed) arm
patients with dose on the Day weeks thereafter after prior VEGFR
on-treatment PK 29 and Day 57 inhibitor therapy samples) visits PK,
pharmacokinetic; po, oral; qd, once daily; RCC, renal cell
carcinoma; NA, not applicable .sup.acabozantinib tablet dose in
free base equivalents; .sup.bdetermined by independent radiology
committee
[0879] Two-hundred eighty two (282) RCC pts received 60 mg
cabozantinib qd (single steady-state sample on Days 29 and 57).
Sixty three (63) healthy volunteers received a single 20, 40 or 60
mg cabozantinib dose (21 samples over 21 days post-dose).
[0880] Covariates were evaluated for effects on apparent plasma
clearance (CL/F) and apparent volume of distribution of the central
compartment (V.sub.c/F) (Table 10.2).
TABLE-US-00054 TABLE 10.2 Study XL184-020 XL184-308 Pooled Number
of Subjects 63 318.sup.a,b 381.sup.a,b Age Median 38 62.5 60
(years) Range (19-54) (32-86) (19-86) (Min-Max) Baseline BMI Median
27.7 26.5 26.7 (kg/m.sup.2).sup.a Range (20.6-32.9) (17.1-57.7)
(17.1-57.7) (Min-Max) Baseline Median 47 38 39 Albumin (g/L) Range
(41-53) (17-48) (17-53) (Min-Max) Baseline ALT Median 23 17 18
(U/L) Range (9-59) (5-115) (5-115) (Min-Max) Baseline Median 149
122.5 127 Hemoglobin Range (119-174) (84-181) (84-181) (g/L)
(Min-Max) Baseline Median 135.5 72.6 78.3 Creatinine Range
(86.4-246.7) (20.8-183.6) (20.8-246.7) Clearance (Min-Max) (mL/min)
Baseline Total Median 10.3 7 7 Bilirubin Range (3.4-30.8) (3-21)
(3-30.8) (.mu.mol/L).sup.b (Min-Max) Sex No. Male (%) 33 (52.4) 247
(77.7) 280 (73.5) No. Female (%) 30 (47.6) 71 (22.3) 101 (26.5)
Race No. White (%) 62 (98.4) 257 (80.8) 319 (83.7) No. Black (%) 1
(1.6) 6 (1.9) 7 (1.8) No. Asian (%) 0 (0) 21 (6.6) 21 (54) No.
Other (%) 0 (0) 19 (6.0) 19 (5.0) No. Unknown 0 (0) 15 (4.7) 15
(3.9) (%) .sup.a18 subjects from Study XL184-308 had missing
baseline BMI .sup.b14 subjects from Study XL184-308 had missing
baseline total bilirubin N = number of subjects; BMI = body mass
index; ALT = alanine aminotransferase
[0881] ER models (time-to-event Cox proportional hazard) were
developed to characterize the relationship between various
predicted cabozantinib exposure measures and the relative hazard
for progression-free survival (PFS) based on 172 events in 315 RCC
patients from the METEOR study with at least one measureable
cabozantinib concentration. PFS was modeled for cabozantinib
concentrations of 375, 750, and 1125 ng/mL which correspond to
predicted steady-state average concentrations at dose levels of 20
mg, 40 mg, and 60 mg, respectively. A tumor growth model was
developed to simulate median longitudinal percent change from
baseline tumor diameter at plasma concentrations associated with 20
mg, 40 mg and 60 mg simulated starting dose treatments.
[0882] Results. As provided in FIG. 10.1, a 2-compartment model
with first-order elimination and two parallel (fast and slow),
lagged first-order absorption processes adequately described the
cabozantinib concentration data. In FIG. 10.1: [0883] F1=fraction
of dose in the first depot; [0884] F2=fraction of dose in the
second depot; [0885] Ka=depot 1 absorption rate constant [0886]
Ka2=depot 2 absorption rate constant; [0887] ALAG1=depot 1
absorption lag time; [0888] ALAG2=depot 2 absorption lag time
[0889] Vc/F=apparent volume of distribution (central compartment);
[0890] Vp/F=apparent volume of distribution (peripheral
compartment); [0891] Q/F=apparent flow between plasma (central) and
peripheral compartments; [0892] CL/F=apparent plasma clearance
[0893] FIG. 10.2A, FIG. 10.2B, FIG. 10.2C, and FIG. 10.2D depict
the cabozantinib PopPK goodness of fit plots by study and dose. The
model predicted good fit to exposure data. The final model
parameter estimates are summarized in the Table 10.3. The CL/F,
V.sub.c/F and terminal half-life values for a White male were
estimated to be 2.23 L/hr, 81.5 L, and 99 hours, respectively. The
estimated inter-individual variability of CL/F (% CV)=46%.
TABLE-US-00055 TABLE 10.3 Parameter Estimate (90% CI) Ka
(hr.sup.-1) 0.568 (0.471, 0.684) Ka2 (hr.sup.-1) 0.102 (0.068,
0.154) CL/F (L/hr) 2.23 (2.12, 2.34) Vc/F (L) 81.5 (66.0, 101) Q/F
(L/hr) 14.2 (12.4, 16.2) Vp/F (L) 213 (200, 226) ALAG1 (hr) 0.459
(0.443, 0.476) ALAG2 (hr) 16.8 (15.3, 18.4)
[0894] The covariates listed in Table 10.3 were evaluated for
effects on apparent plasma clearance (CL/F) and apparent volume of
distribution of the central compartment (V.sub.c/F) and the results
are depicted in FIG. 10.3. In FIG. 10.3, Female gender and Asian
race were statistically-significant covariates on CL/F. Female
subjects had 21% lower CL/F compared with male subjects. Asian
subjects had 27% lower CL/F compared with White subjects. No other
covariate evaluated had a significant effect on cabozantinib CL/F
(Table 10.3).
[0895] An Exposure-Response analysis of Progression Free Survival
was performed based on 172 events in 315 RCC patients from the
METEOR study with at least one measureable cabozantinib
concentration. PFS was modeled for cabozantinib concentrations of
375, 750, and 1125 ng/mL which correspond to predicted steady-state
average concentrations at dose levels of 20 mg, 40 mg, and 60 mg,
respectively. The results are depicted in FIG. 10.4. In FIG. 10.4,
exposure values for calculating PFS were a time-varying average
concentration over the previous 3 weeks (updated daily). The solid
line represents the fraction over time of subjects at each modeled
dose level without PD or death. The dashed lines represent 95%
confidence intervals. A statistically significant relationship was
identified between the rate of PFS (PD or death) and the
time-varying average daily cabozantinib concentration. Increases in
cabozantinib concentration were predicted to decrease the rate of
PD or death in a nonlinear manner. The best E.sub.max (maximal
efficacy) model was nonlinear (p<0.001) with EC.sub.50 (half
maximal effective concentration) equal to 100 ng/mL. The predicted
steady-state average cabozantinib concentrations for the modeled 20
mg, 40 mg, and 60 mg dose levels were all above the EC.sub.50. The
confidence intervals overlap for the predicted steady-state
concentrations at all three dose levels, although a dose-related
trend was observed.
[0896] A tumor growth model was developed to simulate median
longitudinal percent change from baseline tumor diameter at plasma
concentrations associated with simulated 20 mg, 40 mg and 60 mg
starting dose treatments. Objective responses (per RECIST version
1.1) were computed at baseline and every 8 weeks for 1 year for
1000 simulated subjects using the longitudinal sum of tumor
diameter predictions. The best fitting model among those tested for
the change in tumor diameter over time is defined in Equation 1.
The initial condition for this system is an estimated parameter for
baseline tumor diameter. Simulations assume no patients dropped out
of the study.
dY dt = k grow Y - ( k dmax + k dmax tol e - k tol t ) Cavg ( EC 50
+ Cavg ) Y Equation .times. .times. 1 ##EQU00003## [0897] where
[0898] dY/dt=the change in tumor diameter per unit time [0899]
k.sub.grow=the first-order growth rate constant [0900]
k.sub.dmax=the maximum non-attenuating drug induced tumor decay
rate [0901] k.sub.dmax_tol=the maximum loss in the decay rate due
to resistance [0902] k.sub.tol=the rate constant which governs the
rate of attenuation [0903] EC.sub.50=the cabozantinib concentration
yielding one-half of the current tumor decay rate [0904] Cavg=the
individual predicted daily average cabozantinib concentration
[0905] FIG. 10.4 depicts the predicted progression free survival
curves for selected average cabozantinib concentrations.
[0906] FIG. 10.5 depicts the median percent change from baseline
tumor diameter for selected simulated starting doses of
cabozantinib. The maximal median reduction in tumor size increased
with increasing simulated starting doses of 20 mg (-4.45%), 40 mg
(-9.1%), and 60 mg (-11.9%).
[0907] Table 10.4 summarizes the best overall response rates for
selected simulated doses of cabozantinib. Responses (per RECIST
version 1.1) were computed at baseline and every 8 weeks for 1 year
for 1000 simulated subjects using the longitudinal sum of tumor
diameter predictions. A higher percentage of subjects achieved an
objective response and a lower percentage of subjects had
progressive disease in the simulated 60 mg dose group relative to
the simulated 40 mg and 20 mg dose groups.
TABLE-US-00056 TABLE 10.4 Simulated Starting Dose Best Overall
Response Rate 20 mg 40 mg 60 mg Objective Response (%) 8.7 15.6
19.1 Complete Response (%) 0.10 0.0 0.0 Partial Response (%) 8.6
15.6 19.1 Stable Disease (%) 81.1 76.3 73.4 Progressive Disease (%)
10.2 8.1 7.5
[0908] Conclusions. The oral clearance, terminal phase volume of
distribution, and terminal half-life were estimated to be 2.23
L/hr, 319 L, and 99 hours, respectively, for a White male subject.
Inter-individual variability of CL/F was estimated to be 46% CV. A
statistically significant relationship was identified between the
rate of progressive disease (PD) or death and the time-varying
average daily C concentration. Increases in C concentration were
predicted to decrease the rate of PD or death in a nonlinear
manner. The best E.sub.max model (p<0.001) was achieved with
EC.sub.50=100 ng/mL, a value below the typical individual predicted
steady-state average concentration at 60 (1125 ng/mL) or 20 (375
ng/mL) mg/day. In addition, female gender and Asian race were
statistically-significant covariates on CL/F, but the small
magnitude of effect was not considered to be
clinically-significant.
[0909] In ER models, a 60 mg simulated starting dose resulted in
improved PFS, reduced tumor growth and increased ORR compared to 40
mg or 20 mg simulated starting doses. ER analysis indicates that
cabozantinib would be effective at the 60 mg starting dose
evaluated in METEOR as well as dose levels of 40 mg and 20 mg
resulting from dose reduction. Thus, based on the ER analysis, C
was efficacious at all doses evaluated in METEOR, including those
resulting from dose reductions, with higher exposures predicted to
correlate with improved PFS.
Example 11
Cabozantinib (C) Exposure-Response (ER) Modeling of Safety
Endpoints in Patients (Pts) with Renal Cell Carcinoma (RCC) in the
Phase 3 METEOR Study
[0910] Background: ER models were previously developed to
characterize the relationship between C exposure and efficacy
endpoints in RCC pts in the phase 3 METEOR study (J Clin Oncol 34,
2016 [suppl; abstr 2565]). Higher C exposure correlated with
decreased tumor size and improved progression-free survival and
objective response rate. Model-based predictions showed that C
would be effective at the 60 mg starting dose evaluated in METEOR
as well as dose levels of 40 and 20 mg resulting from dose
reduction. In the current study, ER models were developed to
characterize the relationship between C exposure and safety
endpoints in RCC pts.
[0911] Methods: The ER analysis included 318 RCC pts who had
received at least one C dose and had at least one measurable C
concentration. Time-to-event Cox proportional hazard ER models were
developed to characterize the relationship between various
individual predicted C exposure measures and the likelihood of dose
modification and 6 specific adverse events (AEs): fatigue/asthenia,
palmar-plantar erythrodysesthesia (PPE), nausea/vomiting, diarrhea,
hypertension, and stomatitis.
[0912] Results: A statistically significant relationship was
identified between individual predicted C clearance (CL/F) and the
rate of dose modification (p<0.0001), with the risk of dose
modification decreasing with increasing CL/F. An increase in
average C concentration was associated with increased risk of
fatigue/asthenia (Grade 3), PPE (Grade .gtoreq.1), hypertension
(systolic blood pressure [BP]>160 mmHg or diastolic BP >100
mmHg), and diarrhea (Grade .gtoreq.3). The predicted hazard ratios
for these AEs were 2.01, 2.21, 1.85, and 1.78, respectively, based
on the predicted steady-stage average C concentration for a 60 mg
dose relative to a 20 mg dose. Statistically significant ER
relationships were not identified for nausea/vomiting (Grade
.gtoreq.3) or stomatitis (Grade .gtoreq.3).
[0913] Conclusions: Based on the ER analysis, higher C exposures
resulting from lower C CL/F are predicted to increase the dose
modification rate. Reduced C exposures resulting from dose
reduction are predicted to decrease the risk of fatigue/asthenia,
PPE, hypertension, and diarrhea while maintaining clinical
benefit.
OTHER EMBODIMENTS
[0914] The foregoing disclosure has been described in some detail
by way of illustration and example, for purposes of clarity and
understanding. The invention has been described with reference to
various specific and preferred embodiments and techniques. However,
it should be understood that many variations and modifications can
be made while remaining within the spirit and scope of the
invention. It will be obvious to one of skill in the art that
changes and modifications can be practiced within the scope of the
appended claims. Therefore, it is to be understood that the above
description is intended to be illustrative and not restrictive. The
scope of the invention should, therefore, be determined not with
reference to the above description, but should instead be
determined with reference to the following appended claims, along
with the full scope of equivalents to which such claims are
entitled.
* * * * *
References