ZOMETA

1
ZOMETA in Prostate Cancer and Solid Tumors
Other Than Prostate Cancer and Breast Cancer
Placebo-Controlled Trials
C

• Matthew Smith, MD, PhD
• Massachusetts General Hospital
• Harvard Medical SchoolBoston, Massachusetts
• Prof. Robert Coleman, MD, FRCP
• Cancer Research Centre
• Weston Park Hospital
• Sheffield, England

2
Placebo-Controlled Trials Study Objective
C

• Demonstrate that ZOMETA is superior to placebo
  for the treatment of bone metastases

3
Placebo-Controlled Trials Study Endpoints (1)
C

• Primary endpoint
• Proportion () of patients experiencing any
  skeletal-related event (SRE) not including
  hypercalcemia of malignancy (HCM)

4
Placebo-Controlled Trials Study Endpoints (2)
C

• Secondary endpoints
• Time to first SRE
• Skeletal morbidity rate (SMR)
• Andersen-Gill multiple event analysis
• Time to first SRE, SMR, and proportion () of
  patients with any SRE (HCM)
• Pain/analgesic scores
• Bone lesion response
• Time to progression of disease
• Safety (including survival)
• Additional 6 mo of survival and serum creatinine
  data

5
Placebo-Controlled Trials Skeletal-Related
Events (SREs)
C

• Pathologic fractures
• Spinal cord compression
• Radiation for bone pain or to treat or prevent
  pathologic fractures or spinal cord compression
• Surgery to bone
• Change of antineoplastic therapy for bone pain in
  prostate cancer
• Hypercalcemia of malignancy (HCM)

6
Placebo-Controlled Trials Preplanned SRE Analysis
C

• Proportion () of patients with an SRE
• Number of patients with SRE divided by number of
  patients in each treatment group
• Time to first SRE
• Time from randomization to first SRE (days)
• Skeletal morbidity rate (SMR)
• Number of SREs divided by time at risk on trial
  (yr)
• Andersen-Gill multiple event analysis
• Time from randomization to each occurrence of
  the events

Skeletal events occurring within 21 days counted
as a single occurrence.
7
Clinical Trials History
C

• Original study design
• ZOMETA (8 mg or 4 mg) versus placebo infused
  over 5 min every 3 wk for 9 (PC/BC) or 15 mo
  (prostate cancer)
• Renal amendment 1 (June 1999)
• Infusion time for ZOMETA increased from 5 min to
  15 min
• Infusion volume increased from 50 mL to 100 mL
• Renal amendment 2 (June 2000)
• 8 mg switched to 4 mg (8/4-mg group)
• Renal function monitoring within 2 wk prior
  toeach dose
• Statistical amendment
• Primary efficacy analysis based on ZOMETA 4 mg
  versus placebo

8
Clinical Trial History Amendment/Patient Accrual
Timeline
29
6/98
12/98
6/99
6/00
12/00
12/99
1/01
Accrual
Treatment and follow-up
9
ZOMETA in Prostate Cancer Placebo-Controlled
Trial (039)
C
10
Prostate Cancer Trial Design (1)
C

• Prostate carcinoma
• Documented bone metastases
• Rising PSA
• Baseline serum testosterone within the castrate
  range (? 50 ng/dL)
• No strong opiate analgesics
• Serum creatinine ? 3.0 mg/dL (265 µmol/L)
• ECOG performance status 0, 1, 2
• Appropriate antineoplastic therapy at study entry

11
Prostate Cancer Trial Design (2)
C

• Stratification
• Presence or absence of any distant metastases at
  initial diagnosis of cancer
• Patients received oral vitamin D 400 IU and
  calcium 500 mg
• Dose and dosing regimen
• ZOMETA 4 mg, 8/4 mg, and placebo
• 5-min amended to 15-min infusion
• Every 3 wk
• 15-mo follow-up

12
Prostate Cancer Demographics and Prognostic
Factors
31

• ZOMETA ZOMETA 4 mg 8/4 mg Placebo
  Demographic factor N 214 N 221 N 208
• Mean age, yr 71.8 71.2 72.2
• Gender, male 100.0 100.0 100.0
• Race, Caucasian, 83.2 84.2 82.7 Black,
  11.2 8.3 9.1
• Performance status
• ECOG 0 - 1, 92.1 91.3 91.3
• Mean FACT-G score 81.0 81.4 82.2
• No metastases atdiagnosis, n 115 134 116
• Metastases at diagnosis, n 99 87 92
• Baseline PSA, median 82 89 61

13
Prostate Cancer Patient Disposition
8
ISE T2-3, 4

• ZOMETA ZOMETA Disposition 4 mg 8/4 mg
  Placebo

Intent-to-treat, N 214 221 208 Completed
studytherapy (15 mo) n 81 62 65
37.9 28.1 31.3
14
Prostate Cancer Reasons for Early Discontinuation
8
ISE T2-3, 4

• Patients,
• ZOMETA ZOMETA 4 mg 8/4 mg Placebo
  Reason for discontinuation N 214 N
  221 N 208

Total discontinued prematurely 62.1 71.9 68.7 Deat
h 11.7 18.1 15.4 Adverse events 17.8 19.9 13.9 Wit
hdrew consent 19.2 22.6 16.8 Unsatisfactory
therapeutic effect 8.9 7.7 16.3 Protocol
violation 0.5 0.0 0.0 Lost to
follow-up 1.9 0.0 2.4 Other 2.4 3.
7 3.8
15
Prostate Cancer Proportion () of Patients With
an SRE
12
P .021
P .222
Percent of patients
N
214
221
208

• ZOMETA 4 mg versus placebo remained significant
  when fractures were excluded

16
Why Was No Dose Effect Observed?Percent Change
From Baseline N-telopeptide (039)
22
CSR 039 T 9-13

• Maximum target inhibition was achieved in the
  ZOMETA 4 mg group

17
Prostate Cancer Combined AnalysisProportion ()
of Patients With an SRE
12
P .041
Percent of patients
N
435
208
18
Prostate Cancer Components of SRE by Month 15
8
ISE T 2-15CSR 039 T9-4
N 214 221 208
19
Prostate Cancer Time to First SRE
15
011 PTF 9.2-1p3 CSR 039 T9-2 CSR 011 T9-3
Median time,
days P-value ZOMETA 4 mg NR
.011 ZOMETA 8/4 mg 363 .491 Placebo 321
ZOMETA 4 mg 214 149 97 70 45 ZOMETA 8/4 mg
221 132 77 46 34 Placebo 208 128 78 43 31
20
Prostate Cancer Mean SMR
C
ZOMETA 8/4 mg
ZOMETA 4 mg
Placebo
P .006
P .143
1.49
1.06
0.8
N
214
221
208
HCM P lt .05 for ZOMETA 4 mg versus placebo
21
Prostate CancerAndersen-Gill Multiple Event
Analysis Time to SRE up to Month 15

• ZOMETA 4 mg
  ZOMETA 8/4 mg
• Hazard 95 CI for Hazard 95 CI
  for ratio hazard ratio ratio hazard ratio
• Placebo 0.643 (0.476, 0.870) 0.847 (0.640, 1.122)

22
Prostate Cancer (039)Proportion of Patients With
an SRE in Patients With Different Types of Bone
Lesions
57
N
26
26
59
63
129
156
21
39
124
23
Prostate Cancer Disease-Related Endpoints
C
Median time, days ZOMETA ZOMETA
P-value, 4 mg 8/4 mg Placebo ZOMETA 4
mg Endpoint N 214 N 221 N 208 vs placebo
Time to progressionof bone lesion,
days 92 89 87 .275 Time to progressionof
disease, days 84 84 84 .771
24
Prostate Cancer Quality-of-Life Endpoints
C

Change from baseline, mean ? SD ZOMETA
ZOMETA 4 mg 8/4 mg Placebo Endpoint (15
mo) N 214 N 221 N 208 Brief pain
inventory score 0.6 ? 2.27 0.3 ? 2.18 0.9
? 2.23 Analgesic score 1.0 ? 1.33 0.9 ?
1.40 1.1 ? 1.49 Performance status (ECOG)
0.9 ? 1.10 1.0 ? 1.16 1.0 ? 1.28 FACT-G
total score 7.4 ? 17.7 7.4 ? 15.4 8.3 ?
17.4
Increased score decline. Increased score
improvement.
25
Prostate Cancer Efficacy Summary
C
Time to Multiple Proportion first SRE Mean
skeletal event analysis with SRE, (hazard
ratio) morbidity rate hazard ratio ZOMETA 4
mg 33 0.669 0.80 0.643N 214P-value
.021 .011 .006 .004 ZOMETA 8/4
mg 38 0.901 1.06 0.847N 221P-value .222 .491 .
143 .247 Placebo 44 1.49 N 208

• ZOMETA decreases skeletal complications in men
  with prostate cancer and bone metastases

26
ZOMETA in Prostate CancerPlacebo-Controlled
Trial (039)
C

• Safety

27
Primary Cause of Death During theTrial or Within
28 Days After Study Drug Termination
8
ISS T5-12

• Patients, n ()
• ZOMETA ZOMETA
• 4 mg 8/4 mg PlaceboCause of death N 214 N
  218 N 208

Neoplasms benign/ malignant 15 (7.0) 18 (8.3) 14
(6.7) Respiratory/thoracic/ mediastinal 3 (1.4)
2 (0.9) 5 (2.4) Cardiac 5 (2.3) 5 (2.3) 8 (3.8) Ge
neral disorders/ administration site
5 (2.3) 1 (0.5) 2 (1.0) Infections/infestations 2
(0.9) 2 (0.9) 4 (1.9) Renal/urinary 0 (0.0) 4 (1.
8) 0 (0.0)
6 mo additional data.
28
Prostate Cancer Survival All Patients
35
039E PTF 10.5-1p3
Median time, days ZOMETA 4 mg 563 P
.087 ZOMETA 8/4 mg 418 P .765 Placebo 469
ZOMETA 4 mg 214 194 162 141 114 95 53 21 10 ZOMETA
8/4 mg 218 197 166 121 91 75 42 12 5 Placebo 208
190 148 119 94 75 37 17 4
6 mo additional data.
29
Prostate Cancer Incidence of Adverse Events (?
15)Regardless of Study Drug Relationship
C
CSR 039 T10-2

Safety-evaluable patients, n () ZOMETA
4 mg ZOMETA 8/4 mg Placebo Preferred term N
214 N 218 N 208 Bone pain 108 (50.5) 133
(61.0) 127 (61.1) Nausea 77 (36.0) 115 (52.8)
77 (37.0) Constipation 72 (33.6) 85 (39.0)
72 (34.6) Fatigue 70 (32.7) 67 (37.0) 53
(25.5) Anemia NOS 57 (26.6) 60 (27.5) 37
(17.8) Myalgia 53 (24.8) 53 (24.3) 37
(17.8) Vomiting NOS 46 (21.5) 64 (29.4) 43
(20.7) Weakness 45 (21.0) 50 (22.9) 40
(19.2) Anorexia 43 (20.1) 55 (25.2) 36
(17.3) Pyrexia 43 (20.1) 48 (22.0) 27
(13.0) Edema lower limb 41 (19.2) 48 (22.0)
27 (13.0) Dizziness (except vertigo) 38 (17.8)
22 (10.1) 24 (11.5) Diarrhea NOS 36 (16.8)
35 (16.1) 32 (15.4) Weight decreased 36
(16.8) 38 (17.4) 26 (12.5)
NOS Not otherwise specified.
30
Prostate CancerNCI Grade 3/4 HematologyElectroly
te and Mineral Changes
8
Vol 166 ISS PTT 5.1-5

• Anemia
• Incidence lt 10 for all treatment groups with a
  higher incidence in the ZOMETA 8/4-mg treatment
  group
• Higher use of red blood cells and erythropoietin
  in the ZOMETA treatment groups
• Electrolyte and mineral adverse events
• Incidence of hypocalcemia lt 2 for all treatment
  groups
• Higher incidence of hypophosphatemia and
  hypermagnesemia in the ZOMETA treatment groups

31
Patients Enrolling After the 15-min Amendment NCI
Grade 3/4 Serum Creatinine Changes
C

• Patients, n () N 257
• ZOMETA ZOMETA 4 mg 8/4 mg Placebo
• N 92 N 87 N 78
• Grade 3 5 (5.4) 2 (2.3) 1 (1.3)
• Grade 4 0 (0.0) 0 (0.0) 0 (0.0)

6 mo additional data.
32
Prostate CancerKaplan-Meier Estimates of First
Serum Creatinine Increase
35
010E1 PTF 10.6-2p1
Percent ofpatients withoutincrease(randomizedp
rior to 15-mininfusionamendment)
n Hazard ratio P-value ZOMETA 4
mg 112 2.033 .048 ZOMETA 8/4 mg 121 4.016
.001 Placebo 121
Percent ofpatients withoutincrease(randomizeda
fter 15-mininfusionamendment)
n Hazard ratio P-value ZOMETA 4 mg 92 1.107
.802 ZOMETA 8/4 mg 87 1.655 .199 Placebo 78
6 mo additional data. 53 of patients
received only 8 mg. 23 of patients received
only 8 mg.
33
Prostate Cancer Safety Summary
C

• Adverse events commonly associated with
  bisphosphonates (fever, myalgias, anemias,
  hypophosphatemia, hypermagnesemia) were reported
  more frequently in the ZOMETA treatment groups
  than in the placebo group
• The risk of renal deterioration was similar
  between ZOMETA 4 mg (15-min infusion) and placebo

34
Prostate Cancer Overall Summary
C

• ZOMETA decreases skeletal complications in men
  with prostate cancer and bone metastases

35
ZOMETA in Solid Tumors Other Than Prostate
Cancer and Breast Cancer (PC/BC)Placebo-Control
led Trial (011)
C

• Prof. Robert Coleman, MD, FRCPCancer Research
  CentreWeston Park HospitalSheffield, England

36
Solid Tumors PC/BC Trial Design (1)
C

• Solid tumors other than prostate and breast
  cancer (PC/BC)
• ? 1 bone metastasis
• Appropriate antineoplastic therapy at study entry
• Serum creatinine ? 3.0 mg/dL (265 µmol/L)
• ECOG performance status 0, 1, 2

37
Solid Tumors PC/BC Trial Design (2)
C

• Stratification
• Non-small cell lung cancer
• Other solid tumors (renal, small cell lung,
  cancer of unknown primary, bladder, colorectal,
  head and neck, etc.)
• Patients received oral vitamin D 400 IU and
  calcium 500 mg
• Dose and dosing regimen
• ZOMETA 4 mg, 8/4 mg, and placebo
• 5-min amended to 15-min infusion
• Every 3 wk
• 9-mo follow-up

38
Solid Tumors PC/BC Demographics and Prognostic
Factors
31

• ZOMETA ZOMETA 4 mg 8/4 mg
  PlaceboDemographic factor N 257 N 266 N
  250
• Mean age, yr 62.2 60.8 62.3
• Gender, male 62.3 69.9 64.8
• Race
• Caucasian, 89.1 89.5 90.4 Black, 5.9
  5.7 4.9
• Performance status
• ECOG 0 - 1, 83.1 82.3 87.0
• Mean FACT-G score 70.1 69.3 70.8
• NSCLC, n 134 139 130
• Other solid tumors, n 123 127 120

39
Solid Tumors PC/BC Patient Disposition
8
ISE T2-3, 4

• ZOMETA ZOMETA
• Disposition 4 mg 8/4 mg Placebo
• Intent-to-treat, N 257 266 250
• Completed studytherapy (9 mo)
• n 68 65 63
• 26.5 24.4 25.2

40
Solid Tumors PC/BC Reasons for Early
Discontinuation
8
ISE T2-3, 4

• Patients,
• ZOMETA ZOMETA 4 mg 8/4 mg Placebo Reason
  for discontinuation N 257 N 266 N 250

Total discontinued prematurely
73.5 75.6 74.8 Death 25.7 28.2 26.4 Adverse
events 19.1 24.4 20.8 Withdrew consent
17.9 13.5 16.8 Unsatisfactory therapeutic
effect 7.0 5.3 8.0 Protocol violation 1.6 0.0 0.0
Lost to follow-up 0.8 1.5 0.0 Other 1.6 2.7 2.8
41
Solid Tumors PC/BC Proportion () of Patients
With an SRETime to First SRE
12
P .127
P .023
Median time,
days
P-value ZOMETA 4 mg 230 .023 ZOMETA 8/4
mg 219 .034 Placebo 163
N 257
N 266
N 250
ZOMETA 4 mg 257 107 62 468/4 mg
266 99 56 40 Placebo 250 81 48 36
42
Solid Tumors PC/BC Components of SRE by Month 9
8
ISE T 2-15 CSR 011 T9-7
N 257 266 250
43
Solid Tumors PC/BC Mean SMR
C
ZOMETA 8/4 mg
ZOMETA 4 mg
Placebo
P .069
P .005
2.52
2.24
Mean SMR/yr
1.55
N
257
266
250
HCM P lt .05 for ZOMETA 4 mg and 8/4 mg versus
placebo.
44
Solid Tumors PC/BC Andersen-Gill Multiple Event
Analysis Time to SRE up to Month 9
C

• ZOMETA 4 mg
  ZOMETA 8/4 mg
• Hazard 95 CI for Hazard 95 CI
  forStratum ratio hazard ratio ratio hazard ratio
• NSCLC
• Placebo 0.729 (0.524, 1.015) 0.530 (0.377,
  0.745)
• Other solid tumors
• Placebo 0.737 (0.493, 1.101) 0.886 (0.605,
  1.298)
• Total
• Placebo 0.732 (0.567, 0.946) 0.687 (0.531,
  0.890)

45
Other Solid Tumors (011)Proportion of Patients
With an SRE in Patients With Different Types of
Bone Lesions
57
N
111
119
104
82
42
51
128
96
40
46
Solid Tumors PC/BC Disease-Related Endpoints
C
Median time, days ZOMETA ZOMETA
P-value, 4 mg 8/4 mg Placebo ZOMETA 4
mg Endpoint N 257 N 266 N 250 vs
placebo Time to progressionof bone lesion,
days 145 238 109 .34 Time to progressionof
disease, days 89 91 84 .117
47
Solid Tumors PC/BC Quality-of-Life Endpoints
C

Change from baseline, mean ? SD ZOMETA
ZOMETA 4 mg 8/4 mg Placebo Endpoint (9
mo) N 257 N 266 N 250 Brief pain inventory
score 0.1 ? 2.36 0.3 ? 2.08 0.3 ?
2.34 Analgesic score 0.3 ? 1.20 0.3 ? 1.18
0.3 ? 1.08 Performance status (ECOG) 0.9 ?
1.22 1.0 ? 1.25 1.1 ? 1.18 FACT-G total
score 4.7 ? 15.7 2.8 ? 16.7 4.9 ? 16.8
Increased score decline. Increased score
improvement.
48
Solid Tumors PC/BC Efficacy Summary
C
Time to Multiple Proportion first SRE Mean
skeletal event analysis with SRE. (hazard
ratio) morbidity rate hazard ratio ZOMETA 4 mg
38 0.728 2.24 0.732N 257P-value .127 .023 .069
.017 ZOMETA 8/4 mg 35 0.741 1.55 0.687N
266P-value .023 .034 .005 .004 Placebo
44 2.52 N 250

• ZOMETA is the first bisphosphonate to demonstrate
  efficacy in decreasing skeletal complications in
  a broad range of solid tumors

49
ZOMETA in Solid Tumors Other Than Prostate
Cancer and Breast Cancer (PC/BC)Placebo-Control
led Trial (011)
C

• Safety

50
Primary Cause of Death During theTrial or Within
28 Days After Study Drug Termination
8
ISS T5-12

• Patients, n ()
• ZOMETA ZOMETA
• 4 mg 8/4 mg PlaceboCause of death N 254 N
  265 N 247

Neoplasms benign/ malignant 33 (13.0) 43 (16.2)
52 (21.1) Respiratory/thoracic/ mediastinal 15 (5
.9) 10 (3.8) 8 (3.2) Cardiac 8 (3.1) 9 (3.4) 3 (1.
2) General disorders/ administration site
3 (1.2) 5 (1.9) 4 (1.6) Infections/infestations 6
(2.4) 6 (2.3) 4 (1.6) Renal/urinary 1 (0.4) 2 (0.
8) 0 (0.0) Hepato-biliary disorders 0 (0.0) 1 (0.4
) 0 (0.0)
6 mo additional data.
51
Solid Tumors PC/BC Survival All Patients
35
011E1 PTF 10.5-1p3
Median time, days ZOMETA 4 mg 203 P
.947 ZOMETA 8/4 mg 189 P .471 Placebo 183
ZOMETA 4 mg 254 173 102 65 36 17 ZOMETA 8/4
mg 265 177 107 73 38 13 Placebo 247 155 92 62 31 1
8
6 mo additional data.
52
Solid Tumors PC/BC Incidence of Adverse Events
(? 15)Regardless of Study Drug Relationship
C

Safety-evaluable patients, n () ZOMETA
4 mg ZOMETA 8/4 mg Placebo Preferred term N
254 N 265 N 247 Bone pain 129 (50.8) 130
(49.1) 145 (58.7) Nausea 116 (45.7) 106 (40.0)
83 (33.6) Anemia NOS 94 (37.0) 82 (30.9) 82
(33.2) Vomiting NOS 91 (35.8) 83 (31.3) 71
(28.7) Constipation 85 (33.5) 76 (28.7) 89
(36.0) Dyspnea NOS 83 (32.7) 90 (34.0) 65
(26.3) Fatigue 79 (31.1) 78 (29.4) 72
(29.1) Pyrexia 67 (26.4) 70 (26.4) 56
(22.7) Weakness 66 (26.0) 67 (25.3) 65
(26.3) Anorexia 58 (22.8) 60 (22.6) 62
(25.1) Edema lower limb 56 (22.0) 53 (20.0)
49 (19.8) Malignant neoplasm aggravated 54
(21.3) 67 (25.3) 56 (22.7) Cough 47 (18.5)
44 (16.6) 38 (15.4) Diarrhea NOS 43 (16.9)
48 (18.1) 44 (17.8) Headache NOS 42 (16.5)
36 (13.6) 26 (10.5) Insomnia NEC 42 (16.5)
38 (14.3) 30 (12.1) Dehydration 40 (15.7)
48 (18.1) 41 (16.6)
NOS Not otherwise specified. NEC Not
elsewhere classified.
53
Solid Tumors PC/BC NCI Grade 3/4
HematologyElectrolyte and Mineral Changes
8
Vol 166 ISS PTT 5.1-5

• Anemia
• Incidence lt 5 for all treatment groups, with a
  slightly higher incidence in the ZOMETA
  treatment groups
• Use of red blood cells and erythropoietin was
  similar for all treatment groups
• Electrolyte and mineral adverse events
• Incidence of hypocalcemia lt 2 for all treatment
  groups
• Higher incidence of hypophosphatemia in the
  ZOMETA treatment groups

54
Patients Enrolling After the 15-min Amendment NCI
Grade 3/4 Serum Creatinine Changes
C

• Patients, n () N 509
• ZOMETA ZOMETA 4 mg 8/4 mg Placebo
• N 165 N 181 N 163
• Grade 3 1 (0.6) 2 (1.1) 3 (1.8)
• Grade 4 2 (1.2) 0 (0.0) 0 (0.0)

6 mo additional data.
55
Solid Tumors PC/BC Kaplan-Meier Estimates of
First Serum Creatinine Increase
35
011E1 PTF 10.6-2p1
Percent ofpatients(randomizedprior to
15-mininfusionamendment)
n Hazard ratio P-value ZOMETA 4 mg 61 3.836
.050 ZOMETA 8/4 mg 55 2.883
.132 Placebo 54
Percent ofpatients(randomizedafter
15-mininfusionamendment)
n Hazard ratio P-value ZOMETA 4 mg 165 1.587
.228 ZOMETA 8/4 mg 181 1.907
.079 Placebo 163
6 mo additional data. 24 of patients received
only 8-mg. 51 of patients received only 8 mg.
56
Solid Tumors PC/BC Safety Summary
C

• Adverse events commonly associated with
  bisphosphonates (hypophosphatemia, anemias) were
  reported more frequently in the ZOMETA treatment
  groups
• Risk of renal deterioration was moderately higher
  in the ZOMETA 4-mg treatment group(15-min
  infusion) than in the placebo group

57
Solid Tumors PC/BC Overall Summary
C

• ZOMETA is the first bisphosphonate to
  demonstrate efficacy in decreasing skeletal
  complications in a broad range of solid tumors
• ZOMETA (4 mg via 15-min infusion) has a safety
  profile similar to i.v. pamidronate 90 mg
  (historical)