Transcript Document 7754752

42
D-1
Bisphosphonate Bone Metastases Trials
Proportion of Patients With Any SRE§
(12, 010)
Patients, %
Treatment
N
3 mo
6 mo
9 mo
12 mo
Pamidronate Study 12
Pam 90 mg
Placebo
198
179
10
21
21
32
24
41
28
44
ZOMETA® Study 010
ZOMETA 4 mg
ZOMETA 8/4 mg
Pam 90 mg
183
160
167
31
31
25
38
39
40
40
45
45
47
49
49
§Intent-to treat.
42
D-2
Bisphosphonate Bone Metastases Trials
Demographic and Prognostic Variables
(12, 010)
Pamidronate Study 12
Placebo
N = 179
ZOMETA
4 mg
N = 183
ZOMETA
8/4 mg
N = 160
Pam
90 mg
N = 167
64.1 ± 9.4
66.0
62.7 ± 10.1
63.0
63.1 ± 10.52
62.0
62.2 ± 11.37
63.0
62.6 ± 11.41
62.0
Time from initial
diagnosis to Visit 2, mo
Mean ± s.d.
30.5 ± 32.2
Median
19.3
27.7 ± 33.5
14.4
18.0 ± 32.24
2.8
13.5 ± 21.75
2.6
17.3 ± 28.62
2.7
Variable
Age, yr
Mean ± s.d.
Median
Pam
90 mg
N = 198
ZOMETA® Study 010
42
D-3
Bisphosphonate Bone Metastases Trials
Proportion of Patients With Pathologic Fractures§
(12, 010)
Pamidronate Study 12:
Proportion of patients with pathologic fracture in the 3 mo prior to study entry
Time from diagnosis
to study entry
N
Without pathologic
fractures, %
With pathologic
fractures, %
 6 mo
115
75
25
> 6 mo
277
90
10
ZOMETA® Study 010: Proportion of pamidronate patients with pathologic fracture
Time from diagnosis
to study entry
Patients, %
6 mo
9 mo
N
3 mo
 6 mo
104
21
38
40
45
> 6 mo
62
15
24
32
37
§Intent-to treat.
13 mo
D-4
54
Patients With Any SRE up to
End-of-Core by Race (010, 011, 039)
Patients, n/N (%)
Study
number
Race
ZOMETA®
4 mg
ZOMETA
8/4 mg
Pam 90 mg/
placebo
White
Black
Other
N = 561
225/493 (46)
10/34 (29)
13/34 (38)
N = 524
206/443 (47)
22/42 (52)
14/39 (36)
N = 555
234/484 (48)
13/43 (30)
10/28 (36)
White
Black
Other
N = 257
91/229 (40)
4/15 (27)
2/13 (15)
N = 266
85/238 (36)
4/15 (27)
3/13 (23)
N = 250
103/226 (46)
4/12 (33)
4/12 (33)
White
Black
Other
N = 214
64/178 (36)
4/24 (17)
3/12 (25)
N = 221
69/186 (37)
7/19 (37)
9/16 (56)
N = 208
77/172 (45)
8/19 (42)
7/17 (41)
010
011
039
29
D-5
ZOMETA® Efficacy in Bone Metastases
ZOMETA® 4 mg
90
50
84
80
80
60
40
20
N=
44
42
0
HCM
(036, 037)
36
Percent with SRE (–HCM)
Percent with CR
100
40
ZOMETA 8/4 mg
Placebo
44
44
44
Pam 90 mg
46 46
38
38
221 208
257 266 250
564 526 558
Solid tumors
–PC/BC
(011)
Breast cancer and
multiple myeloma
(010)
33
35
30
20
10
214
0
Prostate cancer
(039)
PTT 8.2-4
37
Solid Tumors – PC/BC
Antineoplastic Therapies After Start of
Study Drug (011)
D-6
Patients, n (%)
Antineoplastic therapy
ZOMETA®
4 mg
N = 254
Any
Carboplatin
Paclitaxel
Gemcitabine hydrochloride
Cisplatin
192
74
52
39
37
(75.6)
(29.1)
(20.5)
(15.4)
(14.6)
ZOMETA
8/4 mg
N = 265
184
58
58
28
46
(69.4)
(21.9)
(21.9)
(10.6)
(17.4)
Placebo
N = 247
181
65
46
25
41
(73.3)
(26.3)
(18.6)
(10.1)
(16.6)
PTT 8.2-7
37
Breast Cancer and Multiple Myeloma
Frequency Distribution of Antineoplastic
Regimens (010) (1)
Stratum
No. of
regimen
Multiple myeloma, n
0
1
2
3
4
5
ZOMETA®
4 mg
N = 563
186
11 (5.9)
74 (39.8)
43 (23.1)
29 (15.6)
17 (9.1)
12 (6.5)
Patients, n (%)
ZOMETA
8/4 mg
N = 524
160
10 (6.3)
58 (36.3)
43 (26.9)
31 (19.4)
11 (6.9)
7 (4.4)
Pam
90 mg
N = 556
167
11 (6.6)
72 (43.1)
41 (24.6)
21 (12.6)
12 (7.2)
10 (6.0)
D-7
PTT 8.2-7
37
Breast Cancer and Multiple Myeloma
Frequency Distribution of Antineoplastic
Regimens (010) (2)
Stratum
Breast cancer with
chemotherapy, n
No. of
regimen
ZOMETA®
4 mg
N = 563
Patients, n (%)
ZOMETA
8/4 mg
N = 524
Pam
90 mg
N = 556
0
1
2
3
4
5
176
3 (1.7)
53 (30.1)
61 (34.7)
34 (19.3)
11 (6.3)
14 (8.0)
169
5 (3.0)
51 (30.2)
65 (38.5)
22 (13.0)
17 (10.1)
9 (5.3)
179
6 (3.4)
58 (32.4)
56 (31.3)
35 (19.6)
16 (8.9)
8 (4.5)
0
1
2
3
4
5
201
3 (1.5)
93 (46.3)
59 (29.4)
32 (15.9)
7 (3.5)
7 (3.5)
195
1 (0.5)
114 (58.5)
48 (24.6)
19 (9.7)
7 (3.6)
6 (3.1)
210
(1.4)
(43.3)
(32.9)
(16.2)
(3.8)
(2.4)
Breast cancer with
hormonal therapy, n
3
91
69
34
8
5
D-8
PTT 8.2-7
37
Solid Tumors – PC/BC
Frequency Distribution of Antineoplastic
Regimens (011)
Patients, n (%)
Stratum
Non small cell lung cancer, n
Other solid tumors, n
No. of
regimen
ZOMETA®
4 mg
N = 254
ZOMETA
8/4 mg
N = 265
0
1
2
3
4
5
120
20 (16.7)
50 (41.7)
36 (30.0)
9 (7.5)
5 (4.2)
0 (0)
130
29 (22.3)
65 (50.0)
24 (18.5)
6 (4.6)
3 (2.3)
3 (2.3)
0
1
2
3
4
5
134
42 (31.3)
61 (45.5)
22 (16.4)
8 (6.0)
1 (0.7)
0 (0)
135
52 (38.5)
60 (44.4)
17 (12.6)
3 (2.2)
3 (2.2)
0 (0)
Placebo
N = 247
25
67
16
5
3
1
117
(21.4)
(57.3)
(13.7)
(4.3)
(2.6)
(0.9)
41
54
29
4
1
1
130
(31.5)
(41.5)
(22.3)
(3.1)
(0.8)
(0.8)
D-9
D-10
Solid Tumors –PC/BC
Time to First SRE
Deaths and Dropouts Considered SREs (011)
N (%)§
Median time,
days
P-value
vs placebo
ZOMETA® 4 mg
257 (73)
127
.006
ZOMETA 8/4 mg
266 (80)
105
.184
Placebo
250 (82)
85
§Kaplan-Meier estimate of the proportion at Month 9.
D-11
Breast Cancer and Multiple Myeloma
Time to First SRE
Deaths and Dropouts Considered SREs (010)
N (%)§
Median time,
days
P-value
vs Pam 90 mg
ZOMETA® 4 mg
561 (58)
312
.099
ZOMETA 8/4 mg
555 (59)
265
.545
Pam 90 mg
524 (61)
252
§Kaplan-Meier estimate of the proportion at Month 13.
D-12
Prostate Cancer
Time to First SRE
Deaths and Dropouts Considered SREs (039)
N (%)§
Median time,
days
P-value
vs placebo
ZOMETA® 4 mg
214 (66)
337
.030
ZOMETA 8/4 mg
221 (74)
195
.924
Placebo
208 (73)
221
§Kaplan-Meier estimate of the proportion at Month 15.
D-13
Cumulative Incidence Rate of SRE
All Patients§ (039)
Cumulative incudence rate
039 PTF 9.2-52p3
21
1.0
Median time, days
ZOMETA® 4 mg
ZOMETA 8/4 mg
Placebo
0.8
0.6
NR
NR
337
P = .013
P = .357
0.4
0.2
0.0
0
ZOMETA 4 mg
ZOMETA 8/4 mg
Placebo
§Intent-to-treat.
NR = Not reached.
214
221
208
60
180
177
171
120
180
240
300
360
Time after start of study drug, days
149
132
128
113
102
103
97
77
78
85
61
64
70
46
43
420
45
34
31
D-14
Prostate Cancer
Median Serum PSA Level (Observed) (039)
ZOMETA® 4 mg
Median serum PSA,
ng/mL
039 PTF 9.2-56
54
ZOMETA 8/4 mg
Placebo
200
160
120
80
40
0
0
2
4
6
8
10
12
14
16
90
74
77
60
45
49
67
53
51
Time on study, mo
ZOMETA 4 mg
ZOMETA 8/4 mg
Placebo
212
218
200
150
158
145
162
156
152
132
146
139
85
69
72
102
106
102
56
D-15
Prostate Cancer
Total Number of SREs (039)
With 21-day window
SRE (+HCM)
SRE
Pathologic fracture
Vertebral fracture
Nonvertebral fracture
Radiation to bone
Surgery to bone
Spinal cord compression
Change to antineoplastic
therapy
Hypercalcemia
ZOMETA®
4 mg
Without 21-day window
Placebo
ZOMETA
4 mg
Placebo
112
112
34
10
25
65
5
10
155
155
54
20
38
85
8
15
167
167
46
10
36
90
5
13
258
256
84
30
54
130
8
17
13
0
17
2
13
0
17
2
D-16
Cumulative Incidence Rate of SRE
All Patients§ (011)
Median time, days
Cumulative incidence rate
011 PTF 9.2-52p3
20
1.0
ZOMETA® 4 mg
ZOMETA 8/4 mg
Placebo
0.8
314
NR
185
P = .044
P = .037
0.6
0.4
0.2
0.0
0
ZOMETA 4 mg
ZOMETA 8/4 mg
Placebo
§Intent-to-treat.
NR = not reached.
257
266
250
60
120
180
Time after start of study drug, days
173
177
152
107
99
81
62
56
48
240
46
40
36
56
D-17
Solid Tumors –PC/BC
Total Number of SREs (011)
With 21-day window
SRE (+HCM)
SRE
Pathologic fracture
Vertebral fracture
Nonvertebral fracture
Radiation to bone
Surgery to bone
Spinal cord compression
Hypercalcemia
ZOMETA®
4 mg
131
131
48
21
31
79
12
7
0
Without 21-day window
Placebo
ZOMETA
4 mg
Placebo
163
156
63
32
34
101
9
10
8
201
201
69
27
42
112
12
8
0
275
267
95
41
54
153
9
10
8
56
D-18
Breast Cancer and Multiple Myeloma
Total Number of SREs (010)
With 21-day window
SRE (+HCM)
SRE
Pathologic fracture
Vertebral fracture
Nonvertebral fracture
Radiation to bone
Surgery to bone
Spinal cord compression
Hypercalcemia
Without 21-day window
ZOMETA®
4 mg
Pam
90 mg
ZOMETA
4 mg
Pam
90 mg
411
408
301
131
206
105
23
12
7
451
440
292
133
198
143
36
16
14
808
801
622
202
420
141
25
13
7
849
835
584
214
370
196
37
18
14