1. Safety and Efficacy of Denosumab for Giant Cell Tumor of Bone
Jean-Yves Blay1; Sant Chawla2; Leanne Seeger3; Robert Henshaw4; Edwin Choy5; Robert Grimer6; Stefano Ferrari7; Peter Reichardt8; Piotr Rutkowski9; Scott Schuetze10; David Thomas11; Antonio Lopez Pousa12; Yi Qian13; Ira Jacobs13
1University Claude Bernard Lyon I, Lyon, France; 2Sarcoma Oncology Center, Santa Monica, CA, USA; 3Musculoskeletal Radiology, UCLA School of Medicine, Los Angeles, CA, USA; 4Georgetown University College of Medicine, Washington, DC, USA; 5Massachusetts General Hospital, Boston, MA, USA; 6Royal Orthopaedic Hospital, Birmingham, UK; 7Istituti Ortopedici Rizzoli, Bologna, Italy; 8HELIOS Klinik Berlin-Buch, Berlin, Germany; 9Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland; 10University of Michigan, Ann Arbor, MI; 11Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; 12Hospital Sant Pau, Barcelona, Spain; 13Amgen 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 function1
No standard or approved medicinal therapy
Surgical intervention often associated with significant morbidity2
Mendenhall WM, et al. Am J Clin Oncol. 2006;29:96-9.
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
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.
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. Adults or skeletally mature adolescents with GCTB
Study Design 1 8 15 2 3 4 5 6
Months 7 to N
Denosumab 120 mg SC
Adults or skeletally mature adolescents with GCTB
Cohort 1: Surgically unsalvageable GCTB
Cohort 2: Salvageable GCTB with planned surgery
Cohort 3*: Patients who transitioned from previous denosumab GCTB 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
*No loading doses on days 8 and 15
N = number of months on study

7. Results: Study Participation
Patients Enrolled: 282
Cohort 3: 11 patients
0 Discontinued Study
11 on study at interim analysis cutoff date
11 analyzed for efficacy ‡ 11 analyzed for safety‡
Cohort 1: 170 patients
Cohort 2: 101 patients
21 Discontinued Study
2 Complete tumor resection
7 Adverse event
1 Consent withdrawn
1 Disease progression
2 Requirement for alternative therapy
1 Pregnancy
7 Other
20 Discontinued Study
10 Protocol-specific criteria
1 Adverse event
2 Consent withdrawn
2 Disease progression
5 Other
149 on study at interim analysis cutoff date
81 on study at interim analysis cutoff date
169 analyzed for efficacy * 169 analyzed for safety *
100 analyzed for efficacy † 101 analyzed for safety †
*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.

8. Results: Baseline Demographics and Disease 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
Female
102 (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)
1 (9)
Sacrum
42 (25)
4 (4)
2 (18)
Lung
2 (2)
3 (27)
Pelvic bone
23 (14)
12 (12)
0 (0)
Humerus, radius, ulna, or metacarpus
11 (6)
17 (17)
Vertebrae: cervical, thoracic, or lumbar
21 (12)
3 (3)
Skull
7 (4)
Pelvis (soft tissue only)
2 (1)
Other
8 (5)
6 (6)

9. Results: GCTB 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
Primary
48 (28)
63 (62)
2 (18)
Recurrent
122 (72)
38 (38)
9 (82)
Prior GCTB therapies
Surgery
130 (76)
44 (44)
Unknown
Radiation
42 (25)
6 (6)
0 (0)
Chemo/Immunotherapy
24 (14)
2 (2)
IV bisphosphonates
32 (19)
10 (10)
Oral bisphosphonates
7 (4)
1 (1)
IV: intravenous
The median number of doses was 13 (range, 1-33).
The median time on study was 10 months (range, 0-29).

10. Disease Status (Investigator-Determined)
Best Response During the Assessment Period
Cohort 1: Surgically Unsalvageable (N1 = 159*)
Cohort 2: Salvageable, Surgery Planned (N1 = 93*)
N1 = number of enrolled patients who were eligible and received ≥ 1 dose of denosumab and had a disease status evaluation.
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)
Best Response During the Assessment Period
Cohort 1: Surgically Unsalvageable
N1 = 169*
Cohort 2: Salvageable, Surgery Planned
N1 = 100*
N1 = number of enrolled patients who were eligible and received ≥ 1 dose of denosumab.

12. Radiologic Response to Denosumab
Pre-Treatment
Week 19 Post-Treatment
These are CT scans of the left distal femur before and after treatment.

13. Radiologic Response to Denosumab
Baseline
Week 5
Week 37
These are CT scans of the lung before and after treatment.
Post-treatment CT scans showed reductions in the size of the nodule in the right lower lobe (arrow).

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 surgeries
100 26
Major surgeries 44 3
Hemipelvectomy 4
Amputation 17
Joint/prosthesis replacement 9 1
Joint resection 14 2
En bloc resection 37 6
En bloc excision
Marginal excision
Curettage 13 16
Other
No surgery 74
* n = number of patients
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.

15. Adverse Events Patients with Adverse Events, n* (%) All Patients
Any adverse event
236 (84)
Adverse events occurring with > 10% frequency
Arthralgia
55 (20)
Headache
51 (18)
Nausea
48 (17)
Fatigue
45 (16)
Back pain
42 (15)
Pain in extremity
41 (15)
Grade 3,4, or 5 adverse events
50 (18)
Serious adverse events
25 (9)
Adverse events leading to treatment discontinuation
14 (5)
Adverse event of interest
Adjudicated positive ONJ
3 (1)
Resolved†
2 (1)
Hypocalcemia (none serious)
15 (5)
Serious infections
5 (2)
New primary malignancy
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