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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.

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Presentation on theme: "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."— Presentation transcript:

1 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% EdiVoteStartEdiVoteStop 000 Standard 020

2 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% EdiVoteStartEdiVoteStop Standard

3 Denosumab Daniele Santini Medical Oncology Università Campus Bio-Medico Rome May 13, 2011 New Drugs in Cancer Therapy Director: G. Minotti

4 RANKL / RANK / OPG and bone OC precursor osteoblast/stromal cell OPG RANKL RANK OC precursor osteoblast/stromal cell differentiation, fusion, activation and survival of osteoclasts

5 RANK Ligand Is an Essential Mediator of Osteoclast Formation, Function, and Survival Osteoblasts Activated Osteoclast CFU-M Pre-fusion Osteoclast Multinucleated Osteoclast Hormones Growth factors Cytokines RANKL RANK Bone Formation Bone Resorption Adapted from Boyle WJ, et al. Nature. 2003;423: M-CSF CFU-M = colony forming unit macrophage M-CSF = macrophage colony stimulating factor

6 For Internal Use Only. Amgen Confidential. Osteoprotegerin (OPG) Prevents RANK Ligand Binding to RANK and Inhibits Osteoclast Formation, Function, and Survival Hormones Growth factors Cytokines Bone Formation Adapted from Boyle WJ, et al. Nature. 2003;423: Bone Resorption Inhibited Osteoclast Formation, Function, and Survival Inhibited CFU-M Osteoclast Precursor CFU-M = colony forming unit macrophage M-CSF = macrophage colony stimulating factor Osteoblasts RANKL RANK OPG

7 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 resorption 1-3 RANK Ligand OPG Prevents OC activation Promotes OC activation Osteoclast Activity 1 Hofbauer LC, et al. JAMA. 2004;292: Lacey DL, et al. Cell. 1998;93: Boyle WJ, et al. Nature. 2003;423: OC = osteoclast

8 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 KO 4 weeks of age Mouse Functional Genomics Revealed OPG/RANK/RANKL as Key Regulators of Bone Mass

9 Bone Turnover ALP NTX CTX ICTP TURNOVER OSSEO IN CASO DI DEFICIT ESTROGENICO Estrogeni PTH IL-1 IL-6 > RANKL/RANK < OPG

10 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

11 RANKL RANK Ligand Targeting and Vicious Cycle of Bone Destruction Tumor Cells PTHrP IL-6 PGE2 TNF M-CSF Osteoclast Bone BMP PDGF FGFs IGFs TGF-β Osteoblast

12 Pharmacologic Properties of Denosumab Fully human monoclonal antibody IgG 2 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: 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: Model of Denosumab TNF = tumor necrosis factor; TRAIL = TNFα-related apoptosis-inducing Ligand

13 Denosumab Binds RANK Ligand and Inhibits Osteoclast-Mediated Bone Destruction RANKL RANK Denosumab Bone Formation Hormones Growth factors Cytokines Bone Resorption Inhibited Osteoclast Formation, Function, and Survival Inhibited CFU-M Pre-Fusion Osteoclast Provided as an educational resource. Do not copy or distribute. Osteoblasts

14 PDGF, BMPs TGF-β, IGFs FGFs, Ca 2+ RANKL Inhibition May Interrupt The Vicious Cycle of Cancer-Induced Bone Destruction Osteoblasts RANKL RANK Denosumab Tumor Cell Formation Inhibited Apoptotic Osteoclast PTHrP, BMP, TGF-β, IGF, FGF, VEGF, ET1, WNT

15 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

16 Denosumab Oncology Programme Overview Phase 1Phase 2Phase 3 BrCa & MM - PK/PD Breast cancer - PK/PD (Bisphosphonate naïve) 2 Solid tumours & MM - PK/PD ( Bisphosphonate treated) 3,4 Multiple myeloma 5 Giant cell tumour 6 Solid tumours & MM – SRE 11 Breast cancer - SRE 9 Prostate cancer – delay bone mets Prostate cancer – ADT bone loss 8 Breast cancer – AI bone loss 7

17 Denosumab and potential applications in medical oncology Denosumab and SREs in metastatic disease Denosumab and CTIBL Denosumab and adjuvant setting

18 ~ 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: Denosumab 30 mg SC Q4W Denosumab 120 mg SC Q4W Denosumab 180 mg SC Q4W Denosumab 60 mg SC Q12W Denosumab 180 mg SC Q12W Bisphosphonate IV Q4W 25 weeks of treatment Study (Phase II): Breast Cancer Pts With Bone Mets Follow-up at Weeks 33, 45, 57 Screening/ randomization

19 Primary endpoint % change in uNTx/Cr at Week 13 Secondary 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 Denosumab 30 mg SC Q4W Denosumab 120 mg SC Q4W Denosumab 180 mg SC Q4W Denosumab 60 mg SC Q12W Denosumab 180 mg SC Q12W Bisphosphonate IV 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: weeks of treatment Follow-up at Weeks 33, 45, 57 Study (Phase II): Breast Cancer Pts With Bone Mets

20 Study Week Median (Q1, Q3) Change in uNTx/Cr (%) Denosumab 180 mg Q4W Denosumab 60 mg Q12W Denosumab 180 mg Q12W All denosumab IV BP Denosumab 30 mg Q4W Denosumab 120 mg Q4W Lipton A, et al. J Clin Oncol. 2007;25: Lipton A, et al. Clin Cancer Res, 2008; 14: Denosumab suppresses bone turnover and seems to reduce SRE risk similarly to IV BPs Selected phase III dose: 120 mg Q4W

21 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 Treatment With Daily Supplements of Calcium and Vitamin D n = 36 Denosumab 180 mg SC Q12W n = 37 IV BP Q4W Extension/ Follow-up Study Design ( )

22 Fizazi K et al., J Clin Oncol, 10:15-64, 2009 The decrease of uNTx was higher in the denosumab group Median Percent Change From Baseline in uNTx Corrected by Creatinine Visit Week IV BP Q4W (n= 35) Total SC Denosumab (n = 69) SC Denosumab 180 mg Q12W (n = 33) SC Denosumab 180 mg Q4W (n = 36)

23 Fizazi K et al., J Clin Oncol, 10:15-64, 2009 The incidence of SRE was higher in the bisphosphonate group Proportion of Patients With a First On-Study SRE Study Day IV BP Q4W SC Denosumab 180 mg Q4W SC Denosumab 180 mg Q12W Pooled SC Denosumab Group

24 Denosumab VS Zoledronic Acid Phase 3 Clinical Trials in Patients With Advanced Cancer ECCO Meeting 2009 Delay/Prevention of SRE (Skeletal Related Events): : 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) : 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)

25 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

26 Baseline Characteristics Characteristics, n (%) or median Zoledronic Acid (N = 1020) Denosumab (N = 1026) Women1011 (99)1018 (99) Age (years)5657 ECOG status of 0 or 1932 (91)955 (93) Hormone receptor positive726 (71)740 (72) Time from first bone metastasis to randomization (months) 22 Previous SRE373 (37)378 (37) Presence of visceral metastases525 (51)552 (54) Stopeck A. et al. JCO, 2010

27 Time to First On-Study SRE Zoledronic Acid Denosumab Months Subjects at risk Proportion of Subjects Without SRE KM Estimate of Median Months Denosumab Zoledronic acid Not reached 26.5 HR 0.82 (95% CI: 0.71, 0.95) P < (Non-inferiority) P = 0.01 (Superiority)* * Adjusted for multiplicity Stopeck A. et al. JCO, 2010

28 Time to First and Subsequent On- Study SRE* (Multiple Event Analysis) * Events that occurred at least 21 days apart Cumulative Mean Number of SRE Months Total # of Events Denosumab Zoledronic acid Rate Ratio 0.77 (95% CI: 0.66, 0.89) P = Adjusted for multiplicity Stopeck A. et al. JCO, 2010

29 Adverse Events of Interest Event, n (%) Zoledronic Acid (N = 1013) Denosumab (N = 1020) Infectious AEs494 (48.8)473 (46.4) Infectious serious AEs83 (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 failure25 (2.5)2 (0.2) Acute renal failure7 (0.7)1 (< 0.1) Cumulative rate of ONJ 14 (1.4)20 (2.0) Year 15 (0.5)8 (0.8) Year 212 (1.2)19 (1.9) New primary malignancy5 (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

30 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

31 Baseline Characteristics Characteristic, n (%) or median Zoledronic Acid (N = 890) Denosumab (N = 886) Male552 (62)588 (66) Age (years)6160 Primary tumor type Non-small cell lung cancer345 (39)343 (39) Multiple myeloma93 (10)86 (10) Other452 (51)457 (52) ECOG performance status of 0 or (82)748 (84) Time from first bone metastasis to randomization (months) 22 Previous SRE446 (50)440 (50) Presence of visceral metastases448 (50)474 (53) Henry D et al, JCO, 2011

32 Time to First On-Study SRE 1° - HR: 0.84 (95% CI: 0.71–0.98) P = Noninferiority 2° - Unadjusted P = 0.03 Superiority* Adjusted P = 0.06 ZoledronicAcid Subjects at Risk Denosumab W ithout Study Month ZoledronicAcid Denosumab KM Estimate of Median Months Proportion of Subjects Without Skeletal Related Event Henry D et al, JCO, 2011

33 Time to First-and-Subsequent On-Study SRE (Multiple Event Analysis) ZoledronicAcid Denosumab Total # of SREs ° - Rate Ratio: 0.90 (95% CI: 0.77–1.04) P = 0.14 Henry D et al, JCO, 2011

34 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 28 (0.9)10 (1.1) New primary malignancy3 (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

35 Denosumab 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 35 Abbreviations: 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; Hazard ratio (Dmab vs ZOL) P value In favor of Dmab In favor of ZOL < OS 0.2

36 Denosumab and potential applications in medical oncology Denosumab and SREs in metastatic disease Denosumab and CTIBL Denosumab and adjuvant setting

37 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: , 2008

38 * P < versus Placebo Percentage Change (± 95% CI) From Baseline in Lumbar Spine Bone Mineral Density * * * * * 7.6% Difference at Month Months 5.5% Difference at Month 12 Denosumab (N = 123)Placebo (N = 122) Ellis GK et al. J Clin Oncol, 26: , 2008 At 12 and 24 months, lumbar spine BMD increased by 5.5% and 7.6%, respectively, in the denosumab group versus placebo

39 * P < versus Placebo Months Total Hip (Proximal Femur) Percentage Change (± 95% CI) From Baseline in Bone Mineral Density Placebo (N = 122)Denosumab (N = 123) * * * * Distal 1/3 Radius Placebo (N = 106)Denosumab (N =115) * * 3.7% Difference at Month % Difference at Month % Difference at Month % Difference at Month 24 Ellis GK et al. J Clin Oncol, 26: , 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

40 ALGORITMO DECISIONALE NELLA CTIBL AIOM 2011 IN DONNE IN POSTMENOPAUSA CON CR DELLA MAMMELLA Presenza di frattura da fragilità SINO 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 < fattore di rischio T-score <- 1 T-score < fattore di rischio Grado di evidenza II Raccomandazione B DEXA

41 Smith M et al. N Engl J Med, 361:745-55, 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 Denosumab 60 mg SC, Day 1 of Months 6, 12, 18, Placebo 60 mg SC, Day 1 of Months 6, 12, 18, FOLLOWUPFOLLOWUP ENDOFSTUDYENDOFSTUDY Screen/RandomizeTreatmentFollow-up/EOS RANDOMIZATIONRANDOMIZATION Study Month11824 HALT-PC ( ): Denosumab in ADT-Treated Prostate Cancer Secondary Objectives: Efficacy of denosumab compared with placebo on: Fractures and BMD at nonvertebral sites

42 Smith M et al. N Engl J Med, 361:745-55, Denosumab therapy was also associated with significant increases in bone mineral density at all bone sites (P0.001)

43 Smith M et al. N Engl J Med, 361:745-55, Denosumab therapy was also associated with significant decreases of new vertebral fractures at 12, 24, 36 months

44 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 < fattore di rischio T-score <- 1 T-score < fattore di rischio * Evidenza 1 Racc.: A DEXA Grado di evidenza II Raccomandazione B

45 Denosumab and potential applications in medical oncology Denosumab and SREs in metastatic disease Denosumab and CTIBL Denosumab and adjuvant setting

46 RANK is expressed by cancer cells both at primary tumor and at bone metastases PRIMITIVIMETASTASIPRIMITIVIMETASTASI (p=.194) (p=.528) a.confronto primitivi-metastasi considerando tutti i campioni b. confronto primitivi-metastasi considerando solo le coppie metastasi-tumore dorigine Santini D. J Cell Phys, 2010

47 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 expression A 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

48 Immunohistochemical results: 93 primary breast cancer specimens A BD 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

49 RANK expression associates with accelerated bone metastasis RANK negative patients: SDFS of months RANK positive patients: SDFS of 58.9 months Santini D. Plos One, 2011

50 RANK Ligand Inhibition Blocks Tumor-Induced Osteolysis in Breast Cancer Model MDA-231 Intracardiac Model *Significantly different from 0 mg/kg OPG Reproduced from Morony S, et al. Cancer Res. 2001;61(11): with permission of the American Association for Cancer Research. ControlRANK Ligand Inhibition Radiographic Lesions OPG Dose (mg/kg) * * # of OC / mm 2 Tumor Area OPG Dose (mg/kg) * * # Lesions / Mouse

51 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– * *P < 0.05 Paraprotein (g/dL) Control5T33MM + Vehicle 5T33MM + OPG * % Tumor Cells Cumulative Survival Days OPG Control P < 0.02

52 BasalVehicle RANK Ligand Inhibition (RANK:Fc) X-ray Prostate Cancer LuCaP 35 HU / SCID Model, Rx Initiated at 6 Weeks 1 1. Adapted from Zhang J, et al. Cancer Res. 2003;63: Serum PSA as Surrogate Marker for Prostate Tumor Burden BasalVehicleRANK-Fc Treatment PSA (ng/mL), ** *P < 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 *

53 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: Armstrong AP, et al. The Prostate. 2008;68: LNCaP Migration (% Baseline) Du145 Prostate 1 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 Dosed at 100 ng/ml Invasion (%) PC3 Cells *Significantly different from all other treatment groups, P <

54 RANK Ligand induces migration of RANK- expressing cancer cells to bone Jones DH, et al. Nature. 2006;440: *Cell lines used expressed RANK

55 Prevention of Bone Metastases in PC: Phase III 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. N = 1,435 Denosumab 120 mg SC every 4 weeks Placebo Data expected Q Event-driven study: time to bone metastasis or death Primary endpoint: Time to development of bone metastasis or death Secondary endpoint: Time to development of bone metastasis (excluding death) 55 R

56 Prevention of Bone Metastases in PC: Phase III 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. N = 1,435 Denosumab 120 mg SC every 4 weeks Placebo Data expected Q 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 next ASCO, 11 Amgen press release, 2011

57 ABCSG-18 & D-CARE Trials: Dmab in Adjuvant BC Placebo SC q6mo Denosumab 60 mg SC every q6mo N = 3,400 R Follow-up without treatment: 96 mo Treatment duration: 48 mo D-CARE 2 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 yr N = 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 Identifier: NCT R ABCSG-18 1 Primary Objective: Compare the effects of Dmab vs placebo on the rate of first clinical fracture in women with nonmetastatic BC receiving NSAI therapy

58 Approved Indications for Antiresorptive Agents in Oncology Indication Prevention of SREs HCM Multiple Myeloma Breast Cancer Prostate Cancer a Other Solid Tumors 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: and Further information for clodronate and ibandronate is available at and Denosumab prescribing information is available at = US Registration 58

59 I Punti aperti

60 Denosumab e durata della terapia I Punti aperti

61 Rapid Rebound in Osteolysis on Stopping 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): Emphasis added TreatmentOff treatmentRe-treatment PlaceboDenosumab Median µg/mL (Q1, Q3) Time, months –4 – Time, months TreatmentOff treatmentRe-treatment Percentage Change (LS mean ± SE) PlaceboDenosumab 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?

62 Denosumab e rischio di infezioni I Punti aperti

63 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): ; 2. Xgeva (denosumab) injection [package insert]. Thousand Oaks, CA: Amgen Inc., 2010; 3. Henry D, et al. ECCO-ESMO 2009., abstract 20LBA. Study or subgroup Bone 2008 Ellis 2008 Lewiecki 2007 Total P = 0.03 Infection SAEs in osteoporosis trials 1 Long-term safety of Dmab not yet established; in addition to hypocalcemia 2 and infections, New malignancies with Dmab vs ZOL in OST/MM (0.6% vs 0.3%) 3 Cardiovascular toxicity Favors placebo Favors Dmab

64 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

65 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)

66 Thank you very much for your attention

67 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% EdiVoteStartEdiVoteStop 000 Standard 020

68 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% EdiVoteStartEdiVoteStop Standard


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