Abstract #10034
Denosumab safety and efficacy in giant cell
tumor of bone (GCTB): Interim results from a
phase 2 study
Jean-Yves Blay1, Sant Chawla2, Javier Martin Broto3, Edwin Choy4, Martin
Dominkus5, Jacob Engellau6, Robert Grimer7, Robert Henshaw8, Emanuela
Palmerini9, Peter Reichardt10, Piotr Rutkowski11, Keith Skubitz12, David
Thomas13, Yufan Zhao14, Yi Qian14, Ira Jacobs14
1University Claude Bernard Lyon I, Centre Léon Bérard, Department of Medicine, Lyon, France; 2Sarcoma Oncology
Center, Santa Monica, CA, USA; 3Hospital Son Dureta, Palma de Mallorca, Spain; 4Dana Farber/Harvard Cancer Center,
Massachusetts General Hospital, Boston, MA, USA; 5Medizinische Universitaet Wien, Vienna, Austria; 6Skåne
Universitetssjukhus, Lund, Sweden; 7Royal Orthopaedic Hospital, Birmingham, UK; 8Georgetown University College of
Medicine, Washington, DC, USA; 9Istituti Ortopedici Rizzoli, Bologna, Italy; 10HELIOS Klinik Bad Saarow, Bad Saarow,
Germany; 11Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Department of Soft Tissue/Bone
Sarcoma and Melanoma, Warszawa, Poland; 12Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA;
13Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; 14Amgen Inc., Thousand Oaks, CA, USA
BACKGROUND
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Giant cell tumor of bone (GCTB) is an aggressive primary osteolytic bone tumor that causes substantial morbidity.
GCTB typically occurs in young adults between the second and third decades of life, causing localized tenderness
and swelling, reduced joint mobility, and pain that is often severe and intractable.1
GCTB grows rapidly, destroying bone and spreading into surrounding soft tissues.
In the absence of treatment, the natural history of GCTB is continued growth, complete destruction of the
affected bone, and massive tumor formation, all of which can lead to gross physical deformity and possibly loss of
limb.
To date, there is no approved or effective chemotherapeutic or medicinal therapy for GCTB.
Surgical intervention is the only definitive therapy for patients with resectable tumors, but surgery is often
associated with significant morbidity.2, 3
GCTB tumors contain osteoclast-like giant cells that express RANK and stromal cells and RANK ligand (RANKL), a
key mediator of osteoclast formation, activation, function, and survival.4-7
Excessive secretion of RANKL causes an imbalance in bone remodeling in favor of bone breakdown (Figure 1). 8-10
Figure 1. RANKL is a Central Mediator of the Vicious
Cycle of Bone Destruction in GCTB
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Denosumab is a fully human monoclonal antibody to RANKL that binds with high affinity and
specificity to the soluble and cell membrane-bound forms of human RANKL (Figure 2).11
In an initial open-label, proof-of-concept, phase 2 study (N = 37):12
• Tumor response (defined as elimination of at least 90% of giant cells or no radiological
progression of the target lesion up to week 25) was observed in 86% of subjects with
GCTB
• Clinical benefit was reported in 84% of subjects (reduced pain or improvement in
functional status per investigator report)2
A second phase 2 follow-on study is in progress; safety and efficacy results from the
prespecified second interim analysis are reported here.
Figure 2. Denosumab May Interrupt the Vicious Cycle of
GCTB-induced Bone Destruction
OBJECTIVES
Primary study objective
• Report the safety profile of denosumab
Secondary and exploratory study objectives
• Report investigators’ assessments of disease
progression in 2 separate cohorts (Figure 3):
– Cohort 1: Subjects with surgically unsalvageable disease
– Cohort 2: Subjects with surgically salvageable disease for
whom a morbid surgery is planned
• Report the number of subjects in cohort 2 for whom
surgery is no longer required or who are able to
undergo a less morbid surgery than planned
Figure 3. Study Design
Prespecified interim analysis
*Surgical resection may occur at any time during the study based on the clinical judgment of the investigator
†Subjects not achieving a complete resection after surgery may continue to receive denosumab at a dose of 120 mg SC Q4W if clinical
benefit is determined
‡It was strongly recommended that subjects take daily supplementation ≥ 500 mg of supplemental calcium and ≥ 400 IU of vitamin D,
except in the case of pre-existing hypercalcemia
SC: subcutaneous; Q4W: every 4 weeks
Subjects
•
Cohort 1: Subjects with surgically unsalvageable disease (unresectable or metastatic disease; eg, sacral or
spinal GCTB or multiple lesions including pulmonary metastases)
•
Cohort 2: Subjects with surgically salvageable (resectable) disease whose planned on-study surgery is
associated with severe morbidity (eg, joint resection, limb amputation, or hemipelvectomy)
•
Key inclusion criteria
– Adults or skeletally mature adolescents ≥ 12 years of age, with weight ≥ 45 kg
– Pathologically confirmed GCTB ≤1 year before enrollment
– Measurable evidence of active disease ≤1 year before enrollment
– Karnofsky performance status ≥ 50%
• Key exclusion criteria
– Current GCTB-specific treatment (eg, radiation, chemotherapy, or embolization) or bisphosphonates
– Known or suspected current diagnosis of underlying malignancy or Paget’s disease, or known
diagnosis of second malignancy within the past 5 years
– Prior history or current evidence of osteonecrosis/osteomyelitis of the jaw, an active dental or jaw
condition requiring oral surgery or a non-healed dental/oral surgery, or a planned invasive dental
procedure during the course of the study
•
This prespecified interim analysis (data cut-off date, May 21, 2010) reports:
– Safety results for all subjects who received ≥ 1 dose of denosumab
– Efficacy results for subjects who had the opportunity to receive denosumab treatment for ≥ 6
months
RESULTS
Table 1. Subject Disposition and Denosumab Exposure
Cohort 1
N = 112
Cohort 2
N =50
Subjects receiving ≥ 1 dose of denosumab
109
49
Median (Q1, Q3) number of doses received
11 (7, 16)
9 (5, 12)
7.8 (3.8, 13.4)
5.6 (2.0, 9.8)
9 (8)
4 (8)
Median (Q1, Q3) number of months on study
Withdrew from study, n (%)
•Reasons for discontinuation included adverse events (5 subjects), consent withdrawn (2 subjects), and administrative
decision, protocol-specified criteria, disease progression, lost to follow-up, pregnancy, and requirement for alternative
therapy (1 subject each).
• The efficacy assessment included 100 subjects who received at least 1 dose
of denosumab and had the opportunity to be on denosumab treatment for at
least 6 months.
• The safety assessment included 158 subjects who received at least 1 dose of
denosumab.
Table 2. Subject Demographics
Characteristic
Cohort 1
Surgically unsalvageable
N = 112*
Cohort 2
Salvageable, Surgery Planned
N = 50*
Total
N = 162*
Female, n (%)
71 (63)
29 (58)
100 (62)
32 (13, 76)
34 (17, 56)
32 (13, 76)
85 (76)
40 (80)
125 (77)
8 (7)
4 (8)
12 (7)
9 (8)
3 (6)
12 (7)
Age , median (min, max)
Race/ethnicity, n (%)
White/Caucasian
Black or African American
Hispanic or Latino
Asian or other
* Includes
all enrolled subjects
10 (11)
3 (6)
13 (8)
Table 3. Subject Disease Characteristics
Cohort 1
Surgically unsalvageable
N = 112
Cohort 2
Salvageable, Surgery Planned
N = 50
50 -70%
14 (12)
7 (14)
80 -100%
98 (88)
Characteristic
Karnofsky performance status, n (%)
43 (86)
Location of target lesion - n (%)†
7 (6)
32 (64)
Lung
34 (30)
2 (4)
Sacrum
25 (22)
3 (6)
Pelvic bone
16 (14)
4 (8)
Cervical, thoracic, or lumbar vertebrae
11 (10)
1 (2)
Humerus, radius, ulna, or metacarpus
6 (5)
6 (12)
Skull
7 (6)
0 (0)
Thoracic or cervical soft tissue
3 (3)
1 (2)
Pelvis soft tissue
1 (1)
1 (2)
Abdomen
1 (1)
0 (0)
Chemotherapy
22 (20)
2 (4)
Radiation
30 (27)
1 (2)
Surgery
91 (81)
28 (56)
IV bisphosphonates
28 (25)
6 (12)
Femur, tibia, patella/knee, or tarsus
Prior therapies
* Includes
†
all enrolled subjects
In order of frequency; data missing for 1 subject
Safety
Table 4. Adverse Events
Subjects With Events, n (%)
All adverse events (AEs)
Serious AEs
AEs leading to denosumab discontinuation
AEs of Grade 3 or 4†
Deaths‡
AEs reported in ≥ 10% of subjects
Fatigue
All Subjects
N = 158*
126 (80)
11 (7)
6 94)
25 (16)
2 (1)
23 (15)
Back pain
21 (13)
Headache
21 (13)
Pain in extremity
20 (13)
Arthralgia
18 (11)
Nausea
17 (11)
* Includes all subjects who received ≥ 1 dose of denosumab.
† The most frequently reported AE of Grade 3 or 4 was hypophosphatemia, reported in 4 subjects. Two subjects reported back pain, pain
in extremity, or ONJ of Grades 3 or 4. All other AEs of Grade 3 or 4 were reported in 1 subject each.
‡ Deaths were attributed to progression of bone sarcoma and respiratory failure, neither of which was considered treatment related.
•
Hypocalcemia and osteonecrosis of the jaw (ONJ), known risks of denosumab
treatment described in the package insert, occurred at levels consistent with other
denosumab studies; no new risks were identified in subjects with GCTB.
– Hypocalcemia was reported in 7 subjects (4%); no cases were serious.
– Osteonecrosis of the jaw was reported in 3 subjects (1.9%); 2 cases were serious.
Efficacy
Figure 4. No Disease Progression in the Majority of Subjects
Cohort 1
Surgically unsalvageable
N = 73*
60%
60%
Cohort 2
Salvageable, surgery planned
N = 23*
50%
50%
40%
40%
30%
30%
20%
20%
10%
10%
0%
0%
Complete
response
Partial
response
Stable disease
Disease
progression
Complete
response
Partial
response
Stable disease
Disease
progression
* N = the number of subjects for whom disease progression data were available at the time of analysis.
If multiple responses are present in the same time frame for an individual subject, the best response is presented.
Cohort 1
• Based on investigators’ assessment of best disease
responses, there was no disease progression (Figure 4):
– In 72 of the 73 evaluable subjects (99%) in cohort 1
– In 23 of the 23 evaluable subjects (100%) in cohort 2
Cohort 2
• Among 23 cohort-2 subjects who had surgery planned at
baseline, 20 subjects (87%) had no surgery or less morbid
surgery than planned (Table 5).
– 22 subjects (96%) had no surgery during the first 6 months
– 15 (65%) had no surgery during the first 12 months
– 5 of 8 subjects (62%) undergoing surgery had less morbid
procedures than originally planned (Table 5).
Table 5. Most Cohort 2 Subjects Had No Surgery or a
Less Morbid Surgical Procedure Than Planned
Surgical Procedure*
Planned – n (%)
Actual– n (%)
Amputation
2 (9)
0 (0)
Joint/prosthesis replacement
2 (9)
1 (4)
Joint resection
Marginal excision, en bloc
excision or en bloc resection
1 (4)
2 (9)
5 (22)
0 (0)
Curretage
2 (9)
4 (17)
Other†
3 (13)
1 (4)
No surgery
0 (0)
15 (65)
* In order from most morbid to least morbid
† Other skeletal procedures included replacement of proximal tibia, resection of sacral lesion including bone resection, and
pelvic resection.
Summary
• This interim analysis describes 158 adult and adolescent subjects
with GCTB who received treatment with denosumab of an openlabel phase 2 study.
• Many of these subjects had recurrent or unresectable disease and
had received previous treatment with surgery, chemotherapy,
radiotherapy, and IV bisphosphonates.
• Denosumab was well tolerated by these subjects with GCTB and no
new risks were observed in this population.
• For most subjects with surgically unsalvageable disease,
denosumab treatment halted disease progression.
• For most subjects with surgically salvageable disease, denosumab
treatment delayed, eliminated, or reduced the scope of surgery.
• This study is ongoing; denosumab continues to be studied as a
potential treatment alternative for GCTB.
REFERENCES
1.
2.
Mendenhall WM et al. Am J Clin Oncol. 2006;29:96–9.
Malawer M et al. Giant cell tumour of the bone. In: DeVita V et al., eds.
Principles and Practice of Oncology, 8th ed. Philadelphia: Lippincott,
Williams, and Wilkins, 2008.
3. Balke M et al. J Cancer Res Clin Oncol. 2009;135:149–58.
4. Atkins GJ, et al. J Bone Miner Res. 2006; 21:1339–49.
5. Huang L, et al. Am J Pathol. 2000;156:761–7.
6. Kartsogiannis V, et al. Bone. 1999;25:525–34.
7. Roux S, et al. Am J Clin Pathol. 2002; 117:210–6.
8. Burgess TL, et al. J Cell Biol. 1999;145:527–538.
9. Lacey DL, et al. Cell. 1998;93:165–76.
10. Yasuda H, et al. Proc Natl Acad Sci USA.1998;95:3597–3602.
11. Bekker PJ et al. J Bone Miner Res. 2004;19:1059–66.
12. Thomas D et al. Lancet Oncol. 2010;11:275–80.
Disclosures
Funding for the study and assistance with poster preparation was provided by Amgen Inc.
J.Y. Blay has consulted for or received research funding or honoraria from Novartis, Pfizer, GlaxoSmithKline,
Roche, PharmaMar, and ImClone Systems. S.P. Chawla has consulted for or received research funding from
Amgen, ARIAD, Merck, ZIOPHARM Oncology, and Epeius Biotechnologies. E. Choi has consulted for and
received honoraria from Amgen. R. Grimer has received research funding from Amgen. R. Henshaw has
consulted for and received honoraria and research funding from Amgen. K. Skubitz has consulted for or
received research funding from ARIAD, Keryx Biopharmaceuticals, Novartis, Johnson & Johnson, Cellgene, Cell
Therapeutics, Daiichi Sankyo, SMI, Schering-Plough, GlaxoSmithKline, and Bayer, and has provided expert
testimony on behalf of a plaintiff’s attorney. D.M. Thomas has received honoraria from Amgen. J.M. Broto, M.
Dominkus, E .Palmerini, P. Reichardt, and P. Rutkowski have no potential conflicts of interest to disclose. Y. Zhao,
Y. Qian, and I. Jacobs are employees of Amgen Inc. and have received Amgen stock/stock options.