Download 19 Diel Bondronat

Bondronat achieves better outcomes
in metastatic bone disease
Ingo Diel
CGG-Klinik GmbH
Mannheim, Germany
Keypad question 1
What bisphosphonate do you mainly use for treating
metastatic bone disease?
1. Clodronate
2. Pamidronate
3. Zoledronic acid
4. Bondronat
Keypad question 2
Do you consider intravenous or oral
bisphosphonates to be more effective against
skeletal complications from metastatic bone
disease?
1. Intravenous more effective
2. Oral more effective
3. Both the same
What do patients need from their
bisphosphonate?
Prevention of skeletal complications –
a standard of care
Rapid and sustained relief from metastatic bone pain
Favorable safety profile
What do patients need from their
bisphosphonate?
Prevention of skeletal complications –
a standard of care
Rapid and sustained relief from metastatic bone pain
Favorable safety profile
Bondronat prevents bone events
Placebo-controlled, 96-week trials in breast cancer patients
Intravenous
Bondronat
6mg
40*
Oral
Bondronat
50mg
38**
0
10
20
30
40
50
Risk reduction versus placebo (%)
*p=0.0033; **p=0.0001
Tripathy D, et al. Bone 2004;34(Suppl. 1):S91
Markers of bone turnover correlate
with outcome
Reducing markers of
bone resorption with
bisphosphonates
reduces incidence of
skeletal-related events
(SREs)1–3
Bone resorption
Rate of bone
resorption = rate of
bone complications1
High
Low
Low
High
Bone complications
Brown JE, et al. Br J Cancer 2003;89:2031–7
Brown JE, et al. J Natl Cancer Inst 2005;97:59–69
3
Lipton A, et al. J Clin Oncol 2005;23(Suppl. 16S):11S(abstract 532)
1
2
KEY SLIDE 1
Oral Bondronat is as effective as
intravenous zoledronic acid
Multicenter, open-label, 12-week trial in breast cancer patients
Bondronat 50mg (n=128)
Zoledronic acid 4mg (n=126)
S-CTX (ng/mL)
0.8
76%
73%
0.6
0.4
0.2
0
Baseline
Week 12
Baseline
Week 12
Body JJ, et al. J Clin Oncol 2005;23(Suppl. 16S):12S(abstract 534)
What do patients need from their
bisphosphonate?
Prevention of skeletal complications –
a standard of care
Rapid and sustained relief from metastatic bone pain
Favorable safety profile
Long-term relief of metastatic
bone pain with Bondronat
Phase III studies
KEY SLIDE 2
Long-term bone pain relief (up to
2 years) with intravenous Bondronat
Mean change in pain score
from baseline
Phase III study (MF 4265)
0.3
Placebo (n=158)
Bondronat 6mg (n=154)
0.2
0.1
0
–0.1
p<0.001
25%
reduction
–0.2
–0.3
–0.4
–0.5
0
12
24
36
48
60
Time (weeks)
72
84
96
Diel I, et al. Eur J Cancer 2004;40:1704–12
KEY SLIDE 3
Long-term bone pain relief (up to
2 years) with oral Bondronat
Phase III studies (MF 4414/4434)
Mean change in pain score
from baseline
0.3
Placebo (n=277)
Bondronat 50mg (n=287)
0.2
0.1
0
24%
reduction
–0.1
–0.2
p=0.001
–0.3
–0.4
–0.5
0
12
24
36
48
60
Time (weeks)
72
84
96
Body JJ, et al. Pain 2004;111:306–12
Rapid relief of metastatic bone
pain with Bondronat
Phase II studies with loading-dose Bondronat
Loading-dose Bondronat relieves severe
metastatic bone pain
Study design
Open, prospective and non-randomized
Intravenous Bondronat (6mg for 3 consecutive days)
followed by 6mg every 3–4 weeks for 20 weeks
Patients: 53 (metastatic prostate, renal or bladder cancer)
Results
83% of patients had pain relief (≥3-point VAS reduction)
starting on Day 2
25% of patients became pain-free
Heidenreich A, et al. Eur J Cancer 2003;1(Suppl. 5):S270(abstract 897)
Bondronat reduced metastatic bone pain
from urologic cancer
Mean VAS pain score
8
Severe pain
7
6
5
4
3
2
Mild pain
Day 3
1 p<0.001
0
0
14
VAS = 10-point visual
analog scale
28
42
56
70
84
Time (days)
98
112
126
140
Heidenreich A, et al. Eur J Cancer 2003;1(Suppl. 5):S270(abstract 897)
KEY SLIDE 4
8
80
7
70
Cares for oneself
6
60
50
5
>50% of patients bedridden
4
40
3
30
2
20
Day 3
1 p<0.001
10
0
0
14
VAS = 10-point visual
analog scale
28
42
56
70
84
Time (days)
98
112
126
Karnofsky Index
Mean VAS pain score
Bondronat reduced metastatic bone pain
from urologic cancer
0
140
Heidenreich A, et al. Eur J Cancer 2003;1(Suppl. 5):S270(abstract 897)
Ongoing metastatic bone
pain trials with Bondronat
Metastatic bone pain program
Phase III trials to evaluate rapid relief of bone pain
with loading-dose Bondronat
Trials recruiting patients with malignant bone
disease and moderate-to-severe bone pain
(VAS score ≥4)
Primary endpoint is decrease in bone pain
– percentage of responders
Study design
Day 1 2 3
Bon-I-Pain
(n=450)
Bon-O-Pain
(n=450)
22–28
168
Bondronat 6mg x 3
Bondronat 6mg q3–4 w
Zoledronic acid 4mg x 1
+
placebo x 2
Zoledronic acid 4mg q3–4 w
Bondronat 6mg x 3
Oral daily Bondronat 50mg
+
placebo infusion q3–4 w
Zoledronic acid 4mg x 1
+
placebo x 2
Zoledronic acid 4mg q3–4 w
+
oral daily placebo
What do patients need from their
bisphosphonate?
Prevention of skeletal complications –
a standard of care
Rapid and sustained relief from metastatic bone pain
Favorable safety profile
Oral Bondronat is at least as effective
as zoledronic acid, but what about
their safety profiles?
Oral Bondronat is well tolerated versus
zoledronic acid
Multicenter, open-label, 12-week trial in breast cancer patients
Patients (%)
100
75
76
Oral Bondronat (n=137)
Intravenous zoledronic acid (n=137)
65
51
50
22
25
6
8
0
Any AE
AE = adverse event
Serious AEs
Treatment-related AEs
Body JJ, et al. Breast Cancer Res Treat 2005;94
(Suppl. 1):S260(abstract 6035)
Acute-phase reactions due
to aminobisphosphonates
Acute-phase reactions
– IL-mediated pyrexia with bone and/or joint pain
and leucocytosis
Flu-like symptoms
– begin 10 hours after infusion, last 1–2 days
– occurs typically after first infusion
Pyrexia and flu-like symptoms
not a concern with intravenous Bondronat
Multicenter, open-label, 12-week, bone marker trial
in breast cancer or multiple myeloma patients
50
Patients (%)
40
30
26%
20
13%
10
0
i.v. Bondronat 6mg
(n=39)
Possibly or probably related
to treatment
i.v. zoledronic acid 4mg
(n=38)
Bergström B, et al. Davos 2006
What about renal safety?
Keypad question 3
How do renal safety profiles differ between
bisphosphonates?
1. Large difference
2. Moderate difference
3. Minimal/insignificant difference
4. No difference
5. Undecided
Renal toxicity is not a class effect
Bondronat
Zoledronic acid
Protein binding
87%
56%
Renal half-life
24 days
150–200 days
Cumulative
renal toxicity
No
Yes
Renal safety
comparable to
placebo
Yes
No
Intravenous Bondronat renal safety:
96-week phase III trial and follow-up
Study design
Bondronat 6mg infused over 3–4 weeks (n=152)
compared with placebo (n=157)
Pre-specified recording of renal AEs
Post-hoc Kaplan-Meier analysis of time to increase
in serum creatinine
– 0.5mg/dL if baseline <1.4mg/dL
– 1.0mg/dL if baseline >1.4mg/dL, or
– twice the baseline value
Body JJ, et al. Ann Oncol 2003;14:1399–405
Body JJ, et al. Eur J Cancer Care. In press
KEY SLIDE 5
Renal safety of intravenous Bondronat
comparable with placebo
Patients without renal
function deterioration (%)
Deterioration with Bondronat 6mg consistent with placebo (p=0.22, ns)
– at 1 year: 2% vs 4%; at 2 years: 6% vs 12%
100
94%
88%
80
60
40
Bondronat 6mg
Placebo
20
0
0
12
24
36
48
60
72
Study duration (weeks)
84
96
Body JJ, et al. Eur J Cancer Care. In press
Further evidence for intravenous
Bondronat renal safety
Extension of phase III trial1
Patients offered intravenous Bondronat for a further
2 years (n=62, total drug exposure up to 4 years)
No renal AEs or serum creatinine changes of clinical
relevance
Loading-dose studies2,3
No renal safety concerns as with standard dosing in
various cancer types
1
Pecherstorfer M, et al. Ann Oncol 2004;15(Suppl. 3):iii49
2
Mancini I, Body JJ, et al. J Clin Oncol 2004;22:3587–92
3
Heidenreich A, et al. Eur J Cancer 2003;1(Suppl. 5):S270
What are the benefits of Bondronat’s renal
safety for routine clinical practice?
Intravenous Bondronat is simple
Creatinine
clearance
(mL/min)
Initiation dose
of zoledronic
acid (mg)
>60
4.0
50–60
3.5
40–49
3.3
30–39
3.0
Bondronat (mg)
6.0
Zometa (zoledronic acid). European SmPC. Novartis, April 2005
Bondronat (ibandronate). European SmPC. Roche, October 2003
Unchanged renal labeling for Bondronat
No renal function monitoring mandatory for
Bondronat
Can be used in patients with severe renal impairment
(<30mL/min creatinine clearance)
– intravenous 2mg every 3–4 weeks (similar AUC
to 6mg dose)
Bondronat (ibandronate). European SmPC. Roche, October 2003
Implications of Bondronat
renal safety for the patient
No added renal safety risks and complications
Fewer hospital visits for renal management or
monitoring
Reduces risk of bisphosphonate or chemotherapy
discontinuation
Minimizes interaction with concomitant medications
that have renal elimination or toxicity
Improves quality of life
Bondronat achieves better outcomes in
metastatic bone disease: summary
Proven efficacy
Proven efficacy in SREs across tumor types
Unmatched rapid relief of metastatic bone pain
Equivalent bone marker efficacy to zoledronic acid
Favorable safety profile
Well tolerated for up to 4 years of treatment
No renal safety concerns, even with loading-dose
Loading-dose Bondronat . . . it works!
Try it and see for yourself
Questions
Back-up slides
Oral Bondronat and intravenous
zoledronic acid: SRE efficacy
Andersen-Gill (cross-trial comparison)
Bondronat1
Zoledronic acid2
40
30
50
38
p<0.0001
29
p=0.0183
20
10
0
Intravenous
6mg
Oral 50mg
Risk reduction
versus placebo (%)
Risk reduction
versus placebo (%)
50
41
p<0.0001
40
30
20
10
0
Intravenous
4mg
Body JJ, et al. J Clin Oncol 2003;22(Suppl.):46(abstract 184)
2
Kohno N, et al. J Clin Oncol 2005;23:3314–21
1
Bondronat maintains quality of life
Intravenous
Placebo
(n=143)
Bondronat
6mg
(n=137)
Oral
Placebo
(n=277)
Bondronat
50mg
(n=287)
Change from baseline
(global assessment,
EORTC QLQ-C30)
0
Better
–10
–20
–30
p=0.032
–40
–50
p=0.005
Worse
Diel I, et al. Eur J Cancer 2004;40:1704–12
Body JJ, et al. Pain 2004;111:306–12
What about GI side effects
with oral Bondronat?
Side effects with oral Bondronat
are manageable
Phase III studies (MF 4414/4434)
100
Patients (%)
80
Placebo (n=277)
Bondronat 50mg (n=286)*
60
40
20
5.1
9.4
4.7 7.0
1.4 3.5
0.7 2.1
0.7 2.1
0
Hypocalcemia Dyspepsia
*Two serious AEs:
nausea (n=1), duodenal ulcer (n=1)
Diarrhea rate lower than placebo
Nausea
AE
Esophagitis Abdominal
pain
Body JJ, et al. Br J Cancer 2004;90:1133–7
Diel I, et al. Eur J Cancer 2003;1(Suppl. 5):S135(abstract 443)
Further evidence for oral
Bondronat safety
Patients were offered oral Bondronat for a further
2 years (n=115, total drug exposure up to 4 years)
No treatment-related AEs were serious or led to
withdrawal
Similar side-effect profile as main study
McLachlan SA, et al. Support Care Cancer 2004;12:408
Pyrexia and flu-like symptoms*
not a concern with Bondronat
50
Patients (%)
40
27
30
20
10
1
0
Bondronat 50mg
(n=137)
*Possibly or probably related
to treatment during Days 1–3
Zoledronic acid 4mg
(n=137)
Body JJ, et al. Breast Cancer Res Treat 2005;94
(Suppl. 1):S260(abstract 6035)