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Bondronat achieves better outcomesin metastatic bone disease
Ingo DielCGG-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
*p=0.0033; **p=0.0001 Tripathy D, et al. Bone 2004;34(Suppl. 1):S91
40*
38**
IntravenousBondronat
6mg
Risk reduction versus placebo (%)
OralBondronat
50mg
0 10 20 30 40 50
Placebo-controlled, 96-week trials in breast cancer patients
Markers of bone turnover correlatewith outcome
Rate of bone resorption = rate of bone complications1
Reducing markers of bone resorption with bisphosphonates reduces incidence of skeletal-related events (SREs)1–3
1Brown JE, et al. Br J Cancer 2003;89:2031–7 2Brown JE, et al. J Natl Cancer Inst 2005;97:59–69
3Lipton A, et al. J Clin Oncol 2005;23(Suppl. 16S):11S(abstract 532)
High
LowHighLow
Bo
ne
reso
rpti
on
Bone complications
Body JJ, et al. J Clin Oncol 2005;23(Suppl. 16S):12S(abstract 534)
Oral Bondronat is as effective as intravenous zoledronic acid
Multicenter, open-label, 12-week trial in breast cancer patients
S-C
TX
(n
g/m
L)
0.8
0.6
0.4
0.2
0Baseline Week 12 Baseline Week 12
76%73%
Bondronat 50mg (n=128)
Zoledronic acid 4mg (n=126)
KEY SLIDE 1
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 metastaticbone pain with Bondronat
Phase III studies
Long-term bone pain relief (up to2 years) with intravenous Bondronat
Diel I, et al. Eur J Cancer 2004;40:1704–12
Time (weeks)
p<0.001
0.3
0.2
0.1
0
–0.1
–0.2
–0.3
–0.4
–0.5
Mea
n c
han
ge
in p
ain
sco
refr
om
bas
elin
e
0 12 24 36 48 60 72 84 96
Placebo (n=158)
Bondronat 6mg (n=154)
Phase III study (MF 4265)
25%reduction
KEY SLIDE 2
Long-term bone pain relief (up to2 years) with oral Bondronat
Body JJ, et al. Pain 2004;111:306–12
p=0.001
Phase III studies (MF 4414/4434)
Time (weeks)
0.3
0.2
0.1
0
–0.1
–0.2
–0.3
–0.4
–0.5
Mea
n c
han
ge
in p
ain
sco
refr
om
bas
elin
e
0 12 24 36 48 60 72 84 96
Placebo (n=277)
Bondronat 50mg (n=287)
KEY SLIDE 3
24%reduction
Rapid relief of metastatic bonepain 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)
Heidenreich A, et al. Eur J Cancer 2003;1(Suppl. 5):S270(abstract 897)
Bondronat reduced metastatic bone pain from urologic cancer
Mild pain
8
7
6
5
4
3
2
1
0
Mea
n V
AS
pai
n s
core
0 14 28 42 56 70 84 98 112 126 140
Day 3p<0.001
Time (days)
Severe pain
VAS = 10-point visualanalog scale
80
70
60
50
40
30
20
10
0
Karn
ofsky In
dex
8
7
6
5
4
3
2
1
00 14 28 42 56 70 84 98 112 126 140
Day 3p<0.001
Cares for oneself
>50% of patients bedridden
Time (days)
Bondronat reduced metastatic bone pain from urologic cancer
VAS = 10-point visualanalog scale
Mea
n V
AS
pai
n s
core
Heidenreich A, et al. Eur J Cancer 2003;1(Suppl. 5):S270(abstract 897)
KEY SLIDE 4
Ongoing metastatic bonepain 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 22–28 168
Zoledronic acid 4mg q3–4 w
Bondronat 6mg q3–4 w
Oral daily Bondronat 50mg + placebo infusion q3–4 w
Zoledronic acid 4mg q3–4 w +oral daily placebo
Bon-I-Pain(n=450)
Bondronat 6mg x 3
Zoledronic acid 4mg x 1+ placebo x 2
Bon-O-Pain(n=450)
Bondronat 6mg x 3
Zoledronic acid 4mg x 1+ placebo x 2
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 effectiveas zoledronic acid, but what about
their safety profiles?
Treatment-related AEs
Oral Bondronat is well tolerated versus zoledronic acid
Body JJ, et al. Breast Cancer Res Treat 2005;94(Suppl. 1):S260(abstract 6035)
Multicenter, open-label, 12-week trial in breast cancer patients
Serious AEsAny AE
Oral Bondronat (n=137) Intravenous zoledronic acid (n=137)
100
75
50
25
0
Pat
ien
ts (
%) 65
76
6 8
22
51
AE = adverse event
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
Possibly or probably relatedto treatment
Pat
ien
ts (
%)
50
40
30
20
10
0
Pyrexia and flu-like symptomsnot a concern with intravenous Bondronat
Multicenter, open-label, 12-week, bone marker trial in breast cancer or multiple myeloma patients
Bergström B, et al. Davos 2006
i.v. Bondronat 6mg(n=39)
i.v. zoledronic acid 4mg(n=38)
13%
26%
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 No Yesrenal toxicity
Renal safety Yes Nocomparable to placebo
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 increasein 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;14:1399–405Body JJ, et al. Eur J Cancer Care. In press
100
80
60
40
20
00 12 24 36 48 60 72 84 96
Study duration (weeks)
Pat
ien
ts w
ith
ou
t re
nal
fun
ctio
n d
eter
iora
tio
n (
%)
Bondronat 6mgPlacebo
Body JJ, et al. Eur J Cancer Care. In press
Renal safety of intravenous Bondronat comparable with placebo
Deterioration with Bondronat 6mg consistent with placebo (p=0.22, ns)
– at 1 year: 2% vs 4%; at 2 years: 6% vs 12%
94%88%
KEY SLIDE 5
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
1Pecherstorfer M, et al. Ann Oncol 2004;15(Suppl. 3):iii492Mancini I, Body JJ, et al. J Clin Oncol 2004;22:3587–92
3Heidenreich 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
Zometa (zoledronic acid). European SmPC. Novartis, April 2005Bondronat (ibandronate). European SmPC. Roche, October 2003
Creatinine clearance (mL/min)
Initiation dose of zoledronic
acid (mg) Bondronat (mg)
>60 4.0
50–60 3.5
40–49 3.3
30–39 3.0
6.0
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
29p=0.0183
Andersen-Gill (cross-trial comparison)
Ris
k re
du
ctio
n
vers
us
pla
ceb
o (
%)
Intravenous6mg
Oral 50mg
Bondronat1
Ris
k re
du
ctio
nve
rsu
s p
lace
bo
(%
)Intravenous
4mg
Zoledronic acid2
1Body JJ, et al. J Clin Oncol 2003;22(Suppl.):46(abstract 184)2Kohno N, et al. J Clin Oncol 2005;23:3314–21
38p<0.0001
41p<0.0001
50
40
30
20
10
0
50
40
30
20
10
0
Diel I, et al. Eur J Cancer 2004;40:1704–12Body JJ, et al. Pain 2004;111:306–12
Bondronat maintains quality of life
Ch
ang
e fr
om
bas
elin
e(g
lob
al a
sses
smen
t,E
OR
TC
QL
Q-C
30)
Intravenous Oral
p=0.005
p=0.032
Better
Worse
0
–10
–20
–30
–40
–50
Bondronat Bondronat Placebo 6mg Placebo 50mg(n=143) (n=137) (n=277) (n=287)
What about GI side effectswith oral Bondronat?
Side effects with oral Bondronat are manageable
5.1 4.7 1.4 0.7 0.79.4
3.5 2.1 2.17.0
Placebo (n=277) Bondronat 50mg (n=286)*
Pat
ien
ts (
%)
100
80
60
40
20
0Hypocalcemia Dyspepsia Nausea Esophagitis Abdominal
painAE
*Two serious AEs:nausea (n=1), duodenal ulcer (n=1)
Diarrhea rate lower than placeboBody JJ, et al. Br J Cancer 2004;90:1133–7
Diel I, et al. Eur J Cancer 2003;1(Suppl. 5):S135(abstract 443)
Phase III studies (MF 4414/4434)
Further evidence for oralBondronat safety
Patients were offered oral Bondronat for a further2 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
1
27
Pat
ien
ts (
%)
50
40
30
20
10
0Bondronat 50mg
(n=137)Zoledronic acid 4mg
(n=137)
*Possibly or probably relatedto treatment during Days 1–3
Body JJ, et al. Breast Cancer Res Treat 2005;94(Suppl. 1):S260(abstract 6035)