Il denosumab ha dimostrato nel tumore della mammella metastatico a livello osseo di: 1.Essere non...

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

Il denosumab ha dimostrato nel tumore della prostata ormonorefrattario metastatico a livello

osseo di:





25%

25%

25%

25%020

Standard

Denosumab

Daniele Santini

Medical Oncology

Università Campus Bio-Medico

Rome

May 13, 2011

New Drugs in Cancer TherapyDirector: G. Minotti

http://intranet/FotoGallery/Giornata%20della%20Ricerca%202007%20-%2018%20Maggio%202007/pages/Pubblico%20della%20Giornata.htm

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

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

For Internal Use Only. Amgen Confidential.

Osteoprotegerin (OPG) Prevents RANK Ligand Binding to RANK and Inhibits Osteoclast Formation, Function,

and Survival


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

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

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

Bone Turnover

ALPNTXCTXICTP

TURNOVER OSSEO IN CASO DI DEFICIT ESTROGENICO

EstrogeniPTH

IL-1IL-6 > RANKL/RANK

< OPG

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

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

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

Denosumab Binds RANK Ligand and Inhibits Osteoclast-Mediated Bone Destruction

RANKL

RANK

Denosumab

Bone Formation


Bone Resorption Inhibited

Osteoclast Formation, Function, and Survival Inhibited

CFU-M Pre-FusionOsteoclast

Provided as an educational resource. Do not copy or distribute.

Osteoblasts

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

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

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

Denosumab and potential applications in medical oncology

• Denosumab and SREs in metastatic disease

• Denosumab and CTIBL

• Denosumab and adjuvant setting

• ~ 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





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

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






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

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

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)


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)


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

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)

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

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)


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


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

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


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

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)


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


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


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


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

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

* P < 0.0001 versus Placebo

Per

cen

tag

e C

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ge

(± 9

5% C

I) F

rom

Bas

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e in

Lu

mb

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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


Denosumab (N = 123)Placebo (N = 122)


At 12 and 24 months, lumbar spine BMD increased by 5.5% and 7.6%, respectively, in the denosumab group versus placebo

* 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

* *






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

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

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


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)


Denosumab therapy was also associated with significantdecreases of new vertebral fractures at 12, 24, 36 months

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

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

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

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


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


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

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

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

*

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

- ++

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

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

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

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

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

I Punti “aperti”

http://elezioni.myblog.it/media/02/02/2068258534.jpg

http://www.ventimiglia.biz/images/stories/a/Cultura/Storia/150-unita-italia.jpg

Denosumab e durata della terapia




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

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• 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?

Denosumab e rischio di infezioni




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

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

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)

Thank you very much for your attention

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Il denosumab ha dimostrato nel tumore della mammella metastatico a livello osseo di:





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25%

25%

25%

Standard

020

Il denosumab ha dimostrato nel tumore della prostata ormonorefrattario metastatico a livello

osseo di:





25%

25%

25%

25%020

Standard

Il denosumab ha dimostrato nel tumore della mammella metastatico a livello osseo di: 1.Essere non...

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