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Safety and Efficacy of Denosumab for Giant Cell Tumor of Bone Jean-Yves Blay 1 ; Sant Chawla 2 ; Leanne Seeger 3 ; Robert Henshaw 4 ; Edwin Choy 5 ; Robert.

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Presentation on theme: "Safety and Efficacy of Denosumab for Giant Cell Tumor of Bone Jean-Yves Blay 1 ; Sant Chawla 2 ; Leanne Seeger 3 ; Robert Henshaw 4 ; Edwin Choy 5 ; Robert."— Presentation transcript:

1 Safety and Efficacy of Denosumab for Giant Cell Tumor of Bone Jean-Yves Blay 1 ; Sant Chawla 2 ; Leanne Seeger 3 ; Robert Henshaw 4 ; Edwin Choy 5 ; Robert Grimer 6 ; Stefano Ferrari 7 ; Peter Reichardt 8 ; Piotr Rutkowski 9 ; Scott Schuetze 10 ; David Thomas 11 ; Antonio Lopez Pousa 12 ; Yi Qian 13 ; Ira Jacobs 13 1 University Claude Bernard Lyon I, Lyon, France; 2 Sarcoma Oncology Center, Santa Monica, CA, USA; 3 Musculoskeletal Radiology, UCLA School of Medicine, Los Angeles, CA, USA; 4 Georgetown University College of Medicine, Washington, DC, USA; 5 Massachusetts General Hospital, Boston, MA, USA; 6 Royal Orthopaedic Hospital, Birmingham, UK; 7 Istituti Ortopedici Rizzoli, Bologna, Italy; 8 HELIOS Klinik Berlin-Buch, Berlin, Germany; 9 Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland; 10 University of Michigan, Ann Arbor, MI; 11 Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; 12 Hospital Sant Pau, Barcelona, Spain; 13 Amgen Inc., Thousand Oaks, CA, USA

2 Acknowledgements and Disclosures Funding for the study and assistance with presentation preparation was provided by Amgen Inc. J. Y. Blay has received corporate-sponsored research funding from and has served as an advisory board member for Novartis, GSK, Roche, MSD, and PharmaMar. S. Chawla has received corporate-sponsored research funding from and has served as an advisory board member for Amgen, Threshold, Cytrax, GlaxoSmithKline, and Berg Pharma. R. Henshaw has received corporate-sponsored research funding from and has served as an advisory board member for Amgen. E. Choy has received research funding from the Liddy Shriver Sarcoma Initiative and has served as a consultant to Amgen, Sanofi-Aventis, and Biomed Valley Discoveries. S. Ferrari has received funding from Amgen, Molmed, PharmaMar, and Pfizer and received support from Takeda to attend scientific meetings. P. Reichardt has served as an advisory board member for Novartis, Pfizer, Bayer, MSD/Merck, and as a speakers’ bureau member for Novartis, Pfizer, MSD/Merck, Amgen, and PharmaMar. P. Rutkowski has served as an advisory board member for Novartis, Bristol-Myers Squib (BMS), and MSD and as a speaker’s bureau member for Novartis, Pfizer, Roche, BMS, and MSD. D. Thomas has received research support from Amgen Inc. Y. Qian and I. Jacobs are employees of Amgen Inc. and have received Amgen stock/stock options. L. Seeger, R. Grimer, S. Schuetze, and A. Lopez Pousa have no relationships to disclose.

3 Giant Cell Tumor of Bone (GCTB) Locally aggressive, destructive primary bone tumor Causes pain and swelling and impairs mobility and function 1 No standard or approved medicinal therapy Surgical intervention often associated with significant morbidity 2 1.Mendenhall WM, et al. Am J Clin Oncol. 2006;29: Thomas DM, Skubitz KM. Curr Opin Oncol. 2009;21:

4 Denosumab in GCTB GCTB stromal cells, thought to be the neoplastic component of GCTB, express high levels of RANK ligand (RANKL) that stimulate the formation of RANK-positive tumor giant cells from RANK-positive osteoclast precursors. 1-6 High levels of RANKL also stimulate giant cell activation and survival and tumor-induced bone lysis. 3-5 Denosumab is a fully human monoclonal antibody against RANKL. 6 Denosumab inhibits bone destruction by preventing RANKL-mediated formation, activation, and survival of osteoclast-like giant cells. 5 1.Atkins GJ, et al.. J Bone Miner Res. 2006;21: Huang L, et al. Am J Pathol. 2000;156: Roux S, et al. Am J Clin Pathol. 2002;117: Lau YS et al. Hum Pathol. 2005;36:945–54. 5.Branstetter DG et al. Clin Cancer Res 2012; 8(16): Bekker PJ, et al. J Bone Miner Res. 2004;19:

5 Objectives To evaluate the safety profile of denosumab in patients with GCTB treated with denosumab To evaluate time to disease progression in patients with unsalvageable GCTB To evaluate the proportion of denosumab-treated patients with salvageable GCTB who do not require surgery, for whom surgery is delayed, or who are able to undergo a less morbid surgery This prespecified interim analysis includes all eligible patients enrolled between September 9, 2008 and March 25, 2011 (the analysis cut-off date) Additional results from this study are being presented in posters at CTOS: –Results of independent imaging assessments (poster 144) –Effects of denosumab on pain and analgesic use (poster 143)

6 Study Design Denosumab 120 mg SC Months 7 to N Cohort 2: Salvageable GCTB with planned surgery Cohort 1 : Surgically unsalvageable GCTB 6 Adults or skeletally mature adolescents with GCTB Cohort 3*: Patients who transitioned from previous denosumab GCTB study *No loading doses on days 8 and 15 N = number of months on study Primary Endpoint Safety profile of denosumab Key Secondary Endpoints Cohort 1: Time to disease progression Cohort 2: Proportion of patients without any surgery at month 6

7 Results: Study Participation Cohort 1: 170 patients 149 on study at interim analysis cutoff date 169 analyzed for efficacy * 169 analyzed for safety * Cohort 2: 101 patients 20 Discontinued Study 10 Protocol-specific criteria 1 Adverse event 2 Consent withdrawn 2 Disease progression 5 Other 81 on study at interim analysis cutoff date 100 analyzed for efficacy † 101 analyzed for safety † Patients Enrolled: Discontinued Study 2 Complete tumor resection 7 Adverse event 1 Consent withdrawn 1 Disease progression 2 Requirement for alternative therapy 1 Pregnancy 7 Other *In cohort 1, 169 patients received investigational product. † In cohort 2, 101 patients received investigational product, but one cohort 2 patient was ineligible (no written informed consent) and was therefore excluded from the efficacy analysis. ‡ Cohort 3 patients are included in the safety analyses but not in the efficacy analyses in this presentation. Cohort 3: 11 patients 0 Discontinued Study 11 on study at interim analysis cutoff date 11 analyzed for efficacy ‡ 11 analyzed for safety ‡

8 Results: Baseline Demographics and Disease Characteristics Characteristics (All enrolled patients), n (%) Cohort 1 Surgically Unsalvageable N = 170 Cohort 2 Salvageable, Surgery Planned N = 101 Cohort 3 Patients from Previous Study N = 11 Female102 (60)57 (56)5 (45) Age, median (min–max)33 (13–83)34 (16–69)30 (22–63) Location of target lesion Femur, tibia, fibula, or patella/knee 14 (8)57 (56)1 (9) Sacrum42 (25)4 (4)2 (18) Lung42 (25)2 (2)3 (27) Pelvic bone23 (14)12 (12)0 (0) Humerus, radius, ulna, or metacarpus 11 (6)17 (17)1 (9) Vertebrae: cervical, thoracic, or lumbar 21 (12)3 (3)3 (27) Skull7 (4)0 (0) Pelvis (soft tissue only)2 (1)0 (0) Other8 (5)6 (6)1 (9)

9 Results: GCTB Characteristics Characteristics (All enrolled patients), n (%) Cohort 1 Surgically Unsalvageable N = 170 Cohort 2 Salvageable, Surgery Planned N = 101 Cohort 3 Patients from Previous Study N = 11 GCTB disease type Primary48 (28)63 (62)2 (18) Recurrent122 (72)38 (38)9 (82) Prior GCTB therapies Surgery130 (76)44 (44)Unknown Radiation42 (25)6 (6)0 (0) Chemo/Immunotherapy24 (14)2 (2)0 (0) IV bisphosphonates32 (19)10 (10)0 (0) Oral bisphosphonates7 (4)1 (1)0 (0) The median number of doses was 13 (range, 1-33). The median time on study was 10 months (range, 0-29). IV: intravenous

10 Disease Status (Investigator-Determined) N1 = number of enrolled patients who were eligible and received ≥ 1 dose of denosumab and had a disease status evaluation. Cohort 1: Surgically Unsalvageable (N1 = 159*)Cohort 2: Salvageable, Surgery Planned (N1 = 93*) Best Response During the Assessment Period 6 patients (4%) in Cohort 1 experienced disease progression at some time during the assessment period; the median time to disease progression was not reached.

11 Clinical Benefit (Investigator-Determined) N1 = number of enrolled patients who were eligible and received ≥ 1 dose of denosumab. Cohort 1: Surgically Unsalvageable N1 = 169* Cohort 2: Salvageable, Surgery Planned N1 = 100 * Best Response During the Assessment Period

12 Radiologic Response to Denosumab Pre-TreatmentWeek 19 Post-Treatment

13 Radiologic Response to Denosumab BaselineWeek 5Week 37

14 Planned Versus Actual Surgery in Cohort 2 Surgical Procedure, n* (In decreasing order of morbidity) Baseline Planned (N =100) Actual Total (N = 26) All surgeries10026 Major surgeries443 Hemipelvectomy40 Amputation170 Joint/prosthesis replacement91 Joint resection142 En bloc resection376 En bloc excision40 Marginal excision10 Curettage1316 Other11 No surgery074 Of the 71 patients in Cohort 2 who had the opportunity to be on study for ≥6 months, 64 (90%) did not have any surgery by month 6. By the analysis cut-off date, 74 of 100 patients (74%) in Cohort 2 had not undergone surgery. * n = number of patients

15 Adverse Events Patients with Adverse Events, n* (%) All Patients N = 281* Any adverse event236 (84) Adverse events occurring with > 10% frequency Arthralgia55 (20) Headache51 (18) Nausea48 (17) Fatigue45 (16) Back pain42 (15) Pain in extremity41 (15) Grade 3,4, or 5 adverse events50 (18) Serious adverse events25 (9) Adverse events leading to treatment discontinuation14 (5) Adverse event of interest Adjudicated positive ONJ3 (1) Resolved † 2 (1) Hypocalcemia (none serious)15 (5) Serious infections5 (2) New primary malignancy3 (1) Based on Medical Dictionary for Regulatory Activities (MedDRA; version 14.1 and CTCAE version 3.0) * n = number of patients who received ≥ 1 dose of denosumab † By the cutoff date, 2 cases were resolved and 1 case was not resolved

16 Summary The safety profile of denosumab in these patients with GCTB was consistent with that observed in other denosumab trials; no new risks were observed –ONJ and hypocalcemia, known risks of denosumab, were observed at a low rate consistent with that seen in other studies 96% of Cohort 1 patients had no disease progression at any time on study, as determined by the investigator Of 100 patients for whom surgery was planned: –74 had no surgery –16 of 26 had less morbid surgeries than planned Denosumab delayed disease progression, prolonged the time to surgery, and reduced the need for morbid surgery in most patients, representing a potential new treatment option for patients with GCTB


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