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Il denosumab ha dimostrato nel tumore della mammella metastatico a livello osseo di:
1.Essere non inferiore all'acido zoledronico in termini di tempo al primo SRE
2.Essere non inferiore e anche superiore all'acido zoledronico in termini di tempo al primo SRE
3.Essere capace di ridurre l'incidenza del primo e dei successivi SRE in misura identica all'acido zoledronico
4.Indurre un incremento di incidenza di ONJ superiore all'acido zoledronico
25%
25%
25%
25%
Standard
020
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Il denosumab ha dimostrato nel tumore della prostata ormonorefrattario metastatico a livello
osseo di:
1.Essere non inferiore all'acido zoledronico in termini di tempo al primo SRE
2.Essere non inferiore e anche superiore all'acido zoledronico in termini di tempo al primo SRE
3.Essere capace di ridurre l'incidenza del primo e dei successivi SRE in misura identica all'acido zoledronico
4.Indurre un incremento di incidenza di ONJ superiore all'acido zoledronico
25%
25%
25%
25%020
Standard
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Denosumab
Daniele Santini
Medical Oncology
Università Campus Bio-Medico
Rome
May 13, 2011
New Drugs in Cancer TherapyDirector: G. Minotti
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RANKL / RANK / OPG and RANKL / RANK / OPG and bonebone
OC OC precursorprecursor
osteoblast/stromal cellosteoblast/stromal cell
OPGOPG
RANKRANKLL
RANKRANK
OC OC precursorprecursor
osteoblast/stromal cellosteoblast/stromal cell
differentiation, differentiation, fusion, fusion, activation and activation and survival of survival of osteoclastsosteoclasts
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RANK Ligand Is an Essential Mediator of Osteoclast Formation, Function, and Survival
Osteoblasts
Activated Osteoclast
CFU-M Pre-fusionOsteoclast
MultinucleatedOsteoclast
HormonesGrowth factorsCytokines
RANKL
RANK
Bone Formation
Bone ResorptionAdapted from Boyle WJ, et al. Nature. 2003;423:337-342.
M-CSF
CFU-M = colony forming unit macrophageM-CSF = macrophage colony stimulating factor
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For Internal Use Only. Amgen Confidential.
Osteoprotegerin (OPG) Prevents RANK Ligand Binding to RANK and Inhibits Osteoclast Formation, Function,
and Survival
HormonesGrowth factorsCytokines
Bone Formation
Adapted from Boyle WJ, et al. Nature. 2003;423:337-342.
Bone Resorption Inhibited
Osteoclast Formation, Function, and Survival Inhibited
CFU-M OsteoclastPrecursor
CFU-M = colony forming unit macrophageM-CSF = macrophage colony stimulating factor
Osteoblasts
RANKL
RANK
OPG
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RANK Ligand Drives an Increase in Osteoclast Activity
Alterations of the RANK Ligand / OPG ratio are critical in the pathogenesis of bone diseases that result from increased bone resorption1-3
RANK Ligand
OPG
PreventsOC activation
PromotesOC activation
Osteoclast Activity1Hofbauer LC, et al. JAMA. 2004;292:490-5.2Lacey DL, et al. Cell. 1998;93:165-76.3Boyle WJ, et al. Nature. 2003;423:337-42.
OC = osteoclast
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Normal 4 weeks of age
OPG ApoE Tg 8 weeks of age
RANKL KO 4 weeks of age
OPG KO 8 weeks of age
RANK KO4 weeks of age
Mouse Functional Genomics Revealed OPG/RANK/RANKL as Key Regulators of Bone Mass
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Bone Turnover
ALPNTXCTXICTP
TURNOVER OSSEO IN CASO DI DEFICIT ESTROGENICO
EstrogeniPTH
IL-1IL-6 > RANKL/RANK
< OPG
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RANKL
RANK Ligand Targeting and Vicious Cycle of Bone Destruction
Osteoblast
PTHrP
IL-6
PGE2
TNF
M-CSF
BMP
PDGF
FGFs
IGFs
TGF-β
Bone
Osteoclast
Tumor Cells
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RANKL
RANK Ligand Targeting and Vicious Cycle of Bone Destruction
Tumor Cells
PTHrP
IL-6
PGE2
TNF
M-CSFOsteoclast
Bone
BMP
PDGF
FGFs
IGFs
TGF-β
Osteoblast
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Pharmacologic Properties of Denosumab
• Fully human monoclonal antibody
• IgG2 isotype
• High affinity for human RANK Ligand
• High specificity for RANK Ligand– No detectable binding to TNFα,
TNFβ, TRAIL, or CD40L• No neutralizing antibodies
detected in clinical trials to date
Bekker PJ, et al. J Bone Miner Res. 2004;19:1059-1066. Data on file, Amgen.Elliott R, et al. Osteoporos Int. 2007;18:S54. Abstract P149.McClung MR, et al. New Engl J Med. 2006;354:821-31.
Model of Denosumab
TNF = tumor necrosis factor; TRAIL = TNFα-related apoptosis-inducing Ligand
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Denosumab Binds RANK Ligand and Inhibits Osteoclast-Mediated Bone Destruction
RANKL
RANK
Denosumab
Bone Formation
HormonesGrowth factorsCytokines
Bone Resorption Inhibited
Osteoclast Formation, Function, and Survival Inhibited
CFU-M Pre-FusionOsteoclast
Provided as an educational resource. Do not copy or distribute.
Osteoblasts
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PDGF, BMPsPDGF, BMPsTGF-β, IGFsTGF-β, IGFsFGFs, CaFGFs, Ca2+2+
RANKL Inhibition May Interrupt The “Vicious Cycle” of Cancer-Induced Bone Destruction
Osteoblasts
RANKL
RANK
DenosumabTumor Cell
FormationInhibited
Apoptotic Osteoclast
PTHrP, BMP,PTHrP, BMP,TGF-β, IGF, FGF,TGF-β, IGF, FGF,VEGF, ET1, WNTVEGF, ET1, WNT
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Treatment of Bone
Metastases To Prevent SREs
Prolonging Metastasis-Free
Survival
Hormone-Ablative Therapy-Induced
Bone Loss
n~11,000 patients
Oncology Denosumab Phase 3 Registration Programme
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Denosumab Oncology Programme Overview
Phase 1 Phase 2 Phase 3
BrCa & MM - PK/PDBreast cancer - PK/PD
(Bisphosphonate naïve)2
Solid tumours & MM - PK/PD(Bisphosphonate treated)3,4
Multiple myeloma5
Giant cell tumour6
Solid tumours & MM – SRE 11
Breast cancer - SRE9
Prostate cancer – delay bone mets
Prostate cancer – ADT bone loss8
Breast cancer – AI bone loss7
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Denosumab and potential applications in medical oncology
• Denosumab and SREs in metastatic disease
• Denosumab and CTIBL
• Denosumab and adjuvant setting
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• ~ 42 patients per group (N = 255)
• Blinded denosumab• Open-label IV bisphosphonate
comparator• Patients naive to
bisphosphonates• ECOG PS: 0-2
Lipton A, et al. J Clin Oncol. 2007;25:4431-4437.
Denosumab30 mg SC Q4W
Denosumab120 mg SC Q4W
Denosumab180 mg SC Q4W
Denosumab60 mg SC Q12W
Denosumab180 mg SC Q12W
BisphosphonateIV Q4W
25 weeks of treatment
Study 20040113 (Phase II): Breast Cancer Pts With Bone Mets
Follow-up at Weeks 33, 45, 57
Screening/ randomization
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Primary endpoint • % change in uNTx/Cr at Week 13Secondary endpoints• % change in uNTx/Cr at Week 25• Proportion with > 65%
reduction in uNTx/Cr at Weeks 13 and 25
• Proportion experiencing a SRE
• Time to first SRE
Denosumab30 mg SC Q4W
Denosumab120 mg SC Q4W
Denosumab180 mg SC Q4W
Denosumab60 mg SC Q12W
Denosumab180 mg SC Q12W
BisphosphonateIV Q4W
Screening/ randomization
Bisphosphonates used in this study: Zoledronic acid (n = 39) Pamidronate (n = 3)Ibandronate (n = 1)
Lipton A, et al. J Clin Oncol. 2007;25:4431-4437.
25 weeks of treatment
Follow-up at Weeks 33, 45, 57
Study 20040113 (Phase II): Breast Cancer Pts With Bone Mets
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0 25211713952Study Week
-100
-80
-60
-40
-20
0
20
Med
ian
(Q
1, Q
3) C
han
ge
in u
NT
x/C
r (%
)
Denosumab 180 mg Q4WDenosumab 60 mg Q12W
Denosumab 180 mg Q12W
All denosumab
IV BPDenosumab 30 mg Q4W
Denosumab 120 mg Q4W
Lipton A, et al. J Clin Oncol. 2007;25:4431-4437.Lipton A, et al. Clin Cancer Res, 2008; 14:6690-6
Denosumab suppresses bone turnover and seems to reduce SRE risk similarly to IV BPs
Selected phase III dose: 120 mg Q4W
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Fizazi K et al., J Clin Oncol, 10:15-64, 2009
Randomized Phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer and other neoplasms after intravenous bisphosphonates
Patients with bone metastases and elevated uNTx levels despite ongoing IV bisphosphonate therapy
Screening/ Randomization
n = 38 Denosumab 180 mg SC Q4W
25 Weeks of TreatmentWith Daily Supplements of Calcium and Vitamin D
n = 36 Denosumab 180 mg SC Q12W
n = 37 IV BP Q4W
Extension/ Follow-up
Study Design (20040114)
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Fizazi K et al., J Clin Oncol, 10:15-64, 2009
The decrease of uNTx was higher in the denosumab groupM
edia
n P
erce
nt
Ch
ang
e F
rom
Bas
elin
ein
uN
Tx
Co
rrec
ted
by
Cre
atin
ine
Visit Week
2 5 9 13 17 21 25
-100
-80
-60
-40
-20
0
20
40
60
80
100IV BP Q4W (n= 35)
Total SC Denosumab (n = 69)
SC Denosumab 180 mg Q12W (n = 33)
SC Denosumab 180 mg Q4W (n = 36)
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Fizazi K et al., J Clin Oncol, 10:15-64, 2009
The incidence of SRE was higher in the bisphosphonate groupP
rop
ort
ion
of
Pat
ien
ts W
ith
a
Fir
st O
n-S
tud
y S
RE
Study Day
IV BP Q4W
SC Denosumab 180 mg Q4W
SC Denosumab 180 mg Q12W
Pooled SC Denosumab Group
0
0
5
10
15
20
25
30
20 40 60 80 100 120 140 160 180
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Denosumab VS Zoledronic Acid Phase 3 Clinical Trials in Patients With Advanced Cancer
ECCO Meeting 2009
Delay/Prevention of SRE (Skeletal Related Events):
• 20050136: A Randomized, Double-blind, Multicenter, Phase 3 Study of Denosumab Compared With Zoledronic Acid (Zometa®) in the Treatment of Bone Metastases in Advanced Breast Cancer (n=1960)
• 20050244: A Randomized, Double-blind, Multi-Center Phase 3 Trial of Denosumab versus Zoledronic Acid for Bone Metastases in Advanced Solid Tumors and Multiple Myeloma (n=1690)
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Study Design
1° Endpoint
2° Endpoints
• Time to first on-study SRE (non-inferiority)
• Time to first on-study SRE (superiority)• Time to first and subsequent on-study SRE (superiority)
N = 1020 Zoledronic acid 4 mg IV* and SC placebo every 4 weeks
N = 1026 Denosumab 120 mg SC and Placebo IV* every 4 weeks
Supplemental Calcium and Vitamin D
Key Inclusion
Adults with advanced breast cancer and confirmed bone metastases
Key Exclusion
Current or prior intravenous bisphosphonate administration
*IV product dose adjusted for baseline creatinine clearance and subsequent dose intervals determined by serum creatinine (per Zometa® label)
Stopeck A. et al. JCO, 2010
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Baseline Characteristics
Characteristics,n (%) or median
Zoledronic Acid(N = 1020)
Denosumab(N = 1026)
Women 1011 (99) 1018 (99)
Age (years) 56 57
ECOG status of 0 or 1 932 (91) 955 (93)
Hormone receptor positive 726 (71) 740 (72)
Time from first bone metastasis to randomization (months)
2 2
Previous SRE 373 (37) 378 (37)
Presence of visceral metastases 525 (51) 552 (54)
Stopeck A. et al. JCO, 2010
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Time to First On-Study SRE
Zoledronic Acid 1020 829 676 584 498 427 296 191 94 29
Denosumab 1026 839 697 602 514 437 306 189 99 26
MonthsSubjects at risk
0
1.00
Pro
po
rtio
n o
f S
ub
ject
s W
ith
ou
t S
RE
0 3 6 9 12 15 18 21 24 27 30
0.25
0.50
0.75
KM Estimate ofMedian Months
DenosumabZoledronic acid
Not reached26.5
HR 0.82 (95% CI: 0.71, 0.95)P < 0.0001 (Non-inferiority)P = 0.01 (Superiority)*
* Adjusted for multiplicity
Stopeck A. et al. JCO, 2010
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Time to First and Subsequent On-Study SRE* (Multiple Event Analysis)
* Events that occurred at least 21 days apart
0 3 6 9 12 15 18 21 24 27 300
0.5
1.0
1.5
Cu
mu
lati
ve M
ean
Nu
mb
er o
f S
RE
Months
Total # of Events
DenosumabZoledronic acid
474608
Rate Ratio 0.77 (95% CI: 0.66, 0.89)P = 0.001†
† Adjusted for multiplicity Stopeck A. et al. JCO, 2010
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Adverse Events of Interest
Event, n (%)Zoledronic Acid
(N = 1013)Denosumab (N = 1020)
Infectious AEs 494 (48.8) 473 (46.4) Infectious serious AEs 83 (8.2) 71 (7.0) Acute phase reactions (first 3 days) 277 (27.3) 106 (10.4) Potential renal toxicity AEs* 86 (8.5) 50 (4.9)
Renal failure 25 (2.5) 2 (0.2) Acute renal failure 7 (0.7) 1 (< 0.1)
Cumulative rate of ONJ† 14 (1.4) 20 (2.0)Year 1 5 (0.5) 8 (0.8)Year 2 12 (1.2) 19 (1.9)
New primary malignancy 5 (0.5) 5 (0.5)
† P = 0.39
*Includes blood creatinine increased, hypercreatininemia, oliguria, renal impairment, proteinuria, renal failure, urine output decreased, creatinine renal clearance decreased, renal failure acute, renal function test abnormal, anuria, blood urea increased, renal failure chronic
No neutralizing anti-denosumab antibodies were detected
Stopeck A. et al. JCO, 2010
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Study Design
1° Endpoint
2° Endpoints
• Time to first on-study SRE (non-inferiority)
• Time to first on-study SRE (superiority)• Time to first and subsequent on-study SRE (superiority)
N = 890 Zoledronic acid 4 mg IV* and SC placebo every 4 weeks
N = 886 Denosumab 120 mg SC and Placebo IV* every 4 weeks
Supplemental Calcium and Vitamin D
Key Inclusion
Adults with solid tumors and bone metastases (excluding breast and prostate) or multiple myeloma
Key Exclusion
Current or prior intravenous bisphosphonate administration
*IV product dose adjusted for baseline creatinine clearance and subsequent dose intervals determined by serum creatinine (per Zometa® label)
Henry D et al, JCO, 2011
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Baseline Characteristics
Characteristic, n (%) or median Zoledronic Acid (N = 890)
Denosumab (N = 886)
Male 552 (62) 588 (66)Age (years) 61 60Primary tumor type
Non-small cell lung cancer 345 (39) 343 (39)Multiple myeloma 93 (10) 86 (10)Other 452 (51) 457 (52)
ECOG performance status of 0 or 1 728 (82) 748 (84)
Time from first bone metastasis to randomization (months) 2 2
Previous SRE 446 (50) 440 (50)Presence of visceral metastases 448 (50) 474 (53)
Henry D et al, JCO, 2011
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Time to First On-Study SRE
1° - HR: 0.84 (95% CI: 0.71–0.98)P = 0.0007 Noninferiority
2° - Unadjusted P = 0.03 Superiority*Adjusted P = 0.06
ZoledronicAcid
Subjects at Risk
890 578 376 261 194 126 86 47
Denosumab 886 582 387 266 202 134 96 55
Without
Study Month
ZoledronicAcidDenosumab
0
0.25
0.50
0.75
1.00
0 3 6 9 12 15 18 21 24
KM Estimate ofMedian Months
16.320.6
Pro
po
rtio
n o
f S
ub
jec
ts W
ith
ou
tS
ke
leta
l R
ela
ted
Ev
en
t
Henry D et al, JCO, 2011
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Time to First-and-Subsequent On-Study SRE (Multiple Event Analysis)
Cu
mu
lati
ve
Me
an
Nu
mb
er
of
SR
Es
0.0
0.5
1.0
1.5
Study Month
0 3 6 9 12 15 18 21 24 27 30
Zoledronic Acid
Denosumab
Total # of SREs
436
392
2° - Rate Ratio: 0.90 (95% CI: 0.77–1.04)P = 0.14
Henry D et al, JCO, 2011
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Adverse Events of Interest
Event, n (%)Zoledronic Acid
(N = 878)Denosumab
(N = 878)Infectious AEs 349 (39.7) 358 (40.8)Infectious serious AEs 118 (13.4) 128 (14.6)
Acute phase reaction (first 3 days) 127 (14.5) 61 (6.9)
Potential renal toxicity AEs* 96 (10.9) 73 (8.3)
Renal failure 25 (2.8) 20 (2.3)
Acute renal failure 16 (1.8) 11 (1.3)
Cumulative rates of ONJ† 11 (1.3) 10 (1.1)
Year 1 5 (0.6) 4 (0.5)Year 2 8 (0.9) 10 (1.1)
New primary malignancy 3 (0.3) 5 (0.6)
*Includes blood creatinine increased, renal failure, renal failure acute, proteinuria, blood urea increased, renal impairment, urine output decreased, anuria, oliguria, azotaemia, hypercreatininemia, creatinine renal clearance decreased, renal failure chronic, blood creatinine abnormal
No neutralizing anti-denosumab antibodies were detected† P = 1.0
Henry D et al, JCO, 2011
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Denosumab Denosumab Mortality vs ZOL in MM Patients Mortality vs ZOL in MM Patients
• Dmab the risk of death by 2.3-fold vs ZOL, and Dmab is not indicated for prevention of SREs in patients with MM (n = 180)1
35Abbreviations: Dmab, denosumab; MM, multiple myeloma; SRE, skeletal-related event; ZOL, zoledronic acid.
1. Xgeva™ (denosumab) injection, for subcutaneous use [package insert]. Thousand Oaks, CA; Amgen Inc; 2010.
Hazard ratio (Dmab vs ZOL)
0.1 1 2 3 10
P value
In favor of Dmab In favor of ZOL
< .052.26
OS
0.2
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Denosumab and potential applications in medical oncology
• Denosumab and SREs in metastatic disease
• Denosumab and CTIBL
• Denosumab and adjuvant setting
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Study Design:
Multi-center, randomized, double-blind, placebo-controlled study conducted in the United States and Canada
N = 125 Placebo SC every 6 months (x 4 doses)
N = 127 Denosumab 60 mg SC every 6 months (x 4 doses)
Baseline 12 month 24 month
Women Receiving Aromatase Inhibitor Therapy For Hormone-Receptor-Positive, Non-Metastatic Breast Cancer
•T‑score of ‑1.0 to ‑2.5 at lumbar spine, total hip (proximal femur), or femoral neck (osteopenia)
Phase 3 Study of Denosumab in Women Receiving Aromatase Inhibitor Therapy
Ellis GK et al. J Clin Oncol, 26:4875-82, 2008
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* P < 0.0001 versus Placebo
Per
cen
tag
e C
han
ge
(± 9
5% C
I) F
rom
Bas
elin
e in
Lu
mb
ar S
pin
e B
on
e M
iner
al D
ensi
ty
8
6
4
2
0
-2
7
5
3
1
-1
-3
*
**
**
7.6% Differenceat Month 24
1 3 6 12 24Months
5.5% Differenceat Month 12
Denosumab (N = 123)Placebo (N = 122)
Ellis GK et al. J Clin Oncol, 26:4875-82, 2008
At 12 and 24 months, lumbar spine BMD increased by 5.5% and 7.6%, respectively, in the denosumab group versus placebo
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* P < 0.0001 versus Placebo
Months Months
Total Hip (Proximal Femur)
Per
cen
tag
e C
han
ge (
± 95
% C
I) F
rom
Bas
elin
e in
Bon
e M
iner
al D
ens
ity
1 3 6 12 24
4
2
0
-2
5
3
1
-1
Placebo (N = 122) Denosumab (N = 123)
**
**
Distal 1/3 RadiusPlacebo (N = 106) Denosumab (N =115)
12 24
4
2
0
-2
3
1
-1
-3
-4-5
* *
3.7% Differenceat Month 12
4.7% Differenceat Month 24
3.8% Differenceat Month 12
6.1% Differenceat Month 24
Ellis GK et al. J Clin Oncol, 26:4875-82, 2008
At 12 and 24 months, total hip BMD increased by 3.7% and 4.7%, and distal radius BMD increased by 3.8% and 6.1% respectively, in the
denosumab group versus placebo
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ALGORITMO DECISIONALE NELLA CTIBL AIOM 2011IN DONNE IN POSTMENOPAUSA CON CR DELLA MAMMELLA
Presenza di frattura da fragilità
SI NO
TERAPIA CON BP o DENOSUMAB(Secondo le indicazioni della nota 79)
ETA’
< 60 aa 60-75aa > 75aa
DEXA
T-score< -2
TERAPIA BPs o denosumab
T-score <- 1 + 1 fattore di rischio
T-score <- 1T-score < 0 + 1 fattore di rischio
Grado di evidenza IIRaccomandazione B
DEXA
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Smith M et al. N Engl J Med, 361:745-55, 2009.
Primary Endpoint: Percentage Change in Lumbar Spine BMD at Month 24
Key eligibility criteria Prostate cancer
subjects on ADT Subjects ≥ 70 years
of age or < 70 with T-score < -1.0
No previous IV and limited oral BP use
Planned N = 1226
Denosumab60 mg SC, Day 1 of
Months 6, 12, 18, 24 30
Placebo60 mg SC, Day 1 of
Months 6, 12, 18, 24 30
FOLLOW
UP
END
OF
STUDY
Screen/Randomize Treatment Follow-up/EOS
RANDOMIZATION
Study Month 1 18 24
HALT-PC (20040138): Denosumab in ADT-Treated Prostate Cancer
Secondary Objectives: Efficacy of denosumab compared with placebo on: Fractures and BMD at nonvertebral sites
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Smith M et al. N Engl J Med, 361:745-55, 2009.
Denosumab therapy was also associated with significantincreases in bone mineral density at all bone sites
(P≤0.001) (P≤0.001)
(P≤0.001) (P≤0.001)
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Smith M et al. N Engl J Med, 361:745-55, 2009.
Denosumab therapy was also associated with significantdecreases of new vertebral fractures at 12, 24, 36 months
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ALGORITMO DECISIONALE NELLA CTIBL AIOM 2011 IN MASCHI CON CR DELLA PROSTATA
Presenza di frattura da fragilità
SI NO
TERAPIA: DENOSUMAB*
Eventualmente BP Nota 79
ETA’
< 60 aa 60-75aa > 75aa
DEXA
T-score< -2
TERAPIA Denosumab o eventualmente BPs
T-score <- 1 + 1 fattore di rischio
T-score <- 1T-score < 0 + 1 fattore di rischio
* Evidenza 1 Racc.: A
DEXA
Grado di evidenza IIRaccomandazione B
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Denosumab and potential applications in medical oncology
• Denosumab and SREs in metastatic disease
• Denosumab and CTIBL
• Denosumab and adjuvant setting
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RANK is expressed by cancer cells both at primary tumor and at bone metastases
PRIMITIVI METASTASI PRIMITIVI METASTASI
(p= .194) (p= .528)
a. confronto primitivi-metastasi considerando tutti i campioni
b. confronto primitivi-metastasi considerando solo le coppie metastasi-tumore d’origine
Santini D. J Cell Phys, 2010
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RANK and OPG predict overall survival in early breast cancer patients
Santini D. Plos One, 2011
Figure 2 Kaplan–Meier survival curves for overall survival in 295 breast cancer patients according to RANK and OPG expressionA
B
C
Available gene expression datasets from van de Vijver et al, obtained by microarray analysis of tumor specimens from a total of 295 patients with primary breast cancer
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Immunohistochemical results:
93 primary breast cancer specimens A
B D
C
RANK positive breast cancer
RANK negative breast cancer
93 specimens: 77 IDC samples and 15 ILC samples.
RANK overexpression was found in 30 of the 77 (39%) IDC samples and in 8 of the 15 (53%) ILC samples
Santini D. Plos One, 2011
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RANK expression associates with RANK expression associates with accelerated bone metastasisaccelerated bone metastasis
RANK negative patients: SDFS of 105.7 months
RANK positive patients:
SDFS of 58.9 months
Santini D. Plos One, 2011
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RANK Ligand Inhibition Blocks Tumor-Induced Osteolysis in Breast Cancer Model
MDA-231 Intracardiac Model
*Significantly different from 0 mg/kg OPGReproduced from Morony S, et al. Cancer Res. 2001;61(11):4432-6 with permission of the American Association for Cancer Research.
Control RANK Ligand Inhibition
Radiographic Lesions
0 0.3 1 30
60
120
180
OPG Dose (mg/kg)
**
# of
OC
/ m
m2 T
umor
Are
a
OPG Dose (mg/kg)0 0.3 1 3
0
2
4
**
# Le
sion
s /
Mou
se
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RANK Ligand Inhibition Reduces Tumor Burden and Improves Survival in a Mouse Model of Multiple Myeloma
Adapted from Vanderken K, et al. Cancer Res. 2003;63:287–9.
3.0
3.5
2.5
2.0
1.5
1.0
*
*P < 0.05
Par
apro
tein
(g
/dL
)
Control 5T33MM+ Vehicle
5T33MM+ OPG
85
90
80
75
70
65
*
% T
um
or
Cel
ls
Cu
mu
lati
ve S
urv
ival
0 5 10 15 20 25 30 35 40
Days
1.0
0.8
0.6
0.4
0.2
0
OPG
Control
P < 0.02
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Basal VehicleRANK Ligand Inhibition
(RANK:Fc)
X-r
ay
Prostate Cancer LuCaP 35 HU / SCID Model, Rx Initiated at 6 Weeks1
1. Adapted from Zhang J, et al. Cancer Res. 2003;63:7883-7890.
Serum PSA as Surrogate Marker for Prostate Tumor Burden
0
5
10
15
20
25
30
35
40
Basal Vehicle RANK-FcTreatment
PS
A (
ng
/mL
)
†,**
*P < 0.001 as compared with basal group †P < 0.01 as compared with basal group**P < 0.01 as compared with vehicle treated group
Osteoblastic bone metastases
The Effect of RANK Ligand Inhibition on Established Prostate Cancer-Induced Osteoblastic Bone Lesions in Mice
*
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The Effect of RANK Ligand Inhibition on Migration/Invasion of Malignant Prostate Cancer Cells Expressing RANK (PC-3)
1. Adapted from Jones DH, et al. Nature. 2006;440:692-696. 2. Armstrong AP, et al. The Prostate. 2008;68:92-104.
0
60
120
180
240
LNCaP
Mig
rati
on
(%
Bas
elin
e)
Du145
Prostate1
RANK Ligand (2.5 mcg/mL)RANK Ligand + OPG (10 mcg/mL)
Significantly reduced migration compared to RANK Ligand (a, P < 0.02; b, P < 0.05)
*
OPG†
RANKL†
0
- + - +-
† Dosed at 100 ng/ml2
20
40
60
80
100
120
Inva
sio
n (
%)
PC
3 C
ells
*Significantly different from all other treatment groups, P < 0.05
- ++
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RANK Ligand induces migration of RANK-expressing cancer cells to bone
Jones DH, et al. Nature. 2006;440:692-696.
*Cell lines used expressed RANK
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PreventionPrevention of Bone Metastases in PC: Phase III of Bone Metastases in PC: Phase III Denosumab Trial (AMG 147) Denosumab Trial (AMG 147)
Prostate cancer (nonmetastatic)
Hormone-refractory disease
High risk of bone metastases
Adequate organ function
Abbreviations: AMG, Amgen; PC, prostate cancer; SC, subcutaneous.
http://www.clinicaltrials.gov/ct2/show/NCT00286091?term=denosumab+in+prevention+of+bone+metastases&rank=4.
N = 1,435Denosumab 120 mg SC every 4 weeks
Placebo
Data expected Q1 2011
Event-driven study:time to bone metastasis or death
Primary endpoint: Time to development of bone metastasis or deathSecondary endpoint: Time to development of bone metastasis (excluding death)
55
R
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PreventionPrevention of Bone Metastases in PC: Phase III of Bone Metastases in PC: Phase III Denosumab Trial (AMG 147) Denosumab Trial (AMG 147)
Prostate cancer (nonmetastatic)
Hormone-refractory disease
High risk of bone metastases
Adequate organ function
Abbreviations: AMG, Amgen; PC, prostate cancer; SC, subcutaneous.
http://www.clinicaltrials.gov/ct2/show/NCT00286091?term=denosumab+in+prevention+of+bone+metastases&rank=4.
N = 1,435Denosumab 120 mg SC every 4 weeks
Placebo
Data expected Q1 2011
Event-driven study:time to bone metastasis or death
56
R
Denosumab increased bone metastasis-free survival by 4.2 months
Final data will presented at n
ext ASCO, 11
Amgen press release, 2011
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ABCSG-18 & D-CARE Trials: Dmab in Adjuvant BCABCSG-18 & D-CARE Trials: Dmab in Adjuvant BC
Placebo SC q6mo
Denosumab 60 mg SC every q6moN = 3,400 R
Follow-up without treatment:96 mo
Treatment duration: 48 moD-CARE2
Primary objective: Bone-metastasis–free survival with denosumab vs placebo
Placebo 120 mg SC monthly x 6 mo, q3mo x 4.5 yr
Dmab 120 mg SC monthly x 6 mo, q3mo x 4.5 yrN = 4,500
Treatment duration: 5 yr
Abbreviations: ABCSG-18, Austrian Breast and Colorectal Cancer Study Group trial 18; BC, breast cancer; Dmab, denosumab; NSAI, nonsteroidal aromatase inhibitor; R, randomisation; SC, subcutaneous.
1. http://www.abcsg.org/trials/trial18.html; 2. http://www.clinicaltrials.gov Identifier: NCT01077154.
R
ABCSG-181
• Primary Objective: Compare the effects of Dmab vs placebo on the rate of first clinical fracture in women with nonmetastatic BC receiving NSAI therapy
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Approved Indications for Approved Indications for Antiresorptive Agents in OncologyAntiresorptive Agents in Oncology
IndicationIndication
Prevention of SREs
HCMMultiple Myeloma
Breast Cancer
Prostate Cancera
Other SolidTumors
Clodronate (oral) Pamidronate (IV) Zoledronic acid (IV) Ibandronate (oral and IV) Denosumab – no = European Registration = Worldwide Registration
Zoledronic acid is currently approved for the prevention of SREs in the metastatic breast cancer setting worldwide, including the Middle East and Asia.a In the United States, prostate cancer must have progressed despite hormone therapy.Abbreviations: HCM, hypercalcemia of malignancy; IV, intravenous; SRE, skeletal-related event.
Prescribing information for pamidronate and zoledronic acid is available at: www.pamidronate.com and www.zometa.com. Further information for clodronate and ibandronate is available at www.bayer.nl/ebbsc/cms/nl/healthcare/bayer_schering_pharma and www.roche.com. Denosumab prescribing information is available at www.amgen.com.
= US Registration
58
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I Punti “aperti”
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Denosumab e durata della terapia
I Punti “aperti”
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Rapid Rebound in Osteolysis on Stopping Rapid Rebound in Osteolysis on Stopping Dmab: Risk of SREs With Missed Doses?Dmab: Risk of SREs With Missed Doses?
Abbreviations: BMD, bone mineral density; Dmab, denosumab; SRE, skeletal-related event.
Reprinted from Miller PD, et al. Bone. 2008;43(2):222-229. Emphasis added.
0 6 12 18 36 4824
0
25
15
10
5
20
30 42
Treatment Off treatment Re-treatment
Placebo Denosumab
Med
ian
µg
/mL
(Q
1, Q
3)
Time, months
483624181260–4
–2
0
2
4
6
8
10
12
14
Time, months
Treatment Off treatment Re-treatment
Per
cen
tag
e C
han
ge
(LS
mea
n ±
SE
)
Placebo Denosumab
61
• Rapid ↑ in osteolysis and ↓ in BMD after stopping Dmab in osteoporosis setting
• What can we expect in bone mets setting, wherein osteolysis rates are higher?
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Denosumab e rischio di infezioni
I Punti “aperti”
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Infections and Other AEs With Dmab ?Infections and Other AEs With Dmab ?
63
Abbreviations: AE, adverse event; Dmab, denosumab; MM, multiple myeloma; OST, other solid tumors; SAE, serious adverse event; ZOL, zoledronic acid.
1. Reprinted from Anastasilakis AD, et al. Horm Metab Res. 2009;41(10):721-729; 2. Xgeva (denosumab) injection [package insert]. Thousand Oaks, CA: Amgen Inc., 2010; 3. Henry D, et al. ECCO-ESMO 2009., abstract 20LBA.
Study orsubgroup
Bone 2008
Ellis 2008
Lewiecki 2007
Total P = 0.03
Infection SAEsin osteoporosis trials1
Long-term safety of Dmab not yet established; in addition to hypocalcemia2 and infections, • New malignancies with Dmab vs ZOL in OST/MM (0.6% vs 0.3%)3
• Cardiovascular toxicity3
0.001 0.1 1 10 1000
Favors placeboFavors Dmab
8.41
2.83
1.96
4.45
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Conclusions
• Denosumab prevents bone mineral loss related to AI therapy in breast and in prostate cancer
• Denosumab prevents vertebral fractures related to ADT in prostate cancer patients
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Conclusions
• Phase III studies of denosumab vs bisphosphonates ongoing in metastatic setting show non inferiority or superior efficacy in term of time to first SRE (breast , prostate and other solid tumours)
• Phase III studies of denosumab are ongoing in adjuvant setting (breast and prostate cancer)
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Thank you very much for your attention
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Il denosumab ha dimostrato nel tumore della mammella metastatico a livello osseo di:
1.Essere non inferiore all'acido zoledronico in termini di tempo al primo SRE
2.Essere non inferiore e anche superiore all'acido zoledronico in termini di tempo al primo SRE
3.Essere capace di ridurre l'incidenza del primo e dei successivi SRE in misura identica all'acido zoledronico
4.Indurre un incremento di incidenza di ONJ superiore all'acido zoledronico
25%
25%
25%
25%
Standard
020
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Il denosumab ha dimostrato nel tumore della prostata ormonorefrattario metastatico a livello
osseo di:
1.Essere non inferiore all'acido zoledronico in termini di tempo al primo SRE
2.Essere non inferiore e anche superiore all'acido zoledronico in termini di tempo al primo SRE
3.Essere capace di ridurre l'incidenza del primo e dei successivi SRE in misura identica all'acido zoledronico
4.Indurre un incremento di incidenza di ONJ superiore all'acido zoledronico
25%
25%
25%
25%020
Standard