Denosumab Safety and Efficacy in Giant Cell Tumor of Bone (GCTB): Interim Results From a Phase

1
Denosumab Safety and Efficacy in Giant Cell Tumor
of Bone (GCTB) Interim Results From a Phase 2
study

• Sant Chawla,1 Jean-Yves Blay,2 Javier Martin
  Broto,3 Edwin Choy,4 Martin Dominkus,5 Jacob
  Engellau,6 Robert Grimer,7 Robert Henshaw,8
  Emanuela Palmerini,9 Peter Reichardt,10 Piotr
  Rutkowski,11 Keith Skubitz,12 David Thomas,13
  Yufan Zhao,14 Yi Qian,14 Ira Jacobs14
• 1Sarcoma Oncology Center, Santa Monica, CA, USA
  2University Claude Bernard Lyon I, Centre Léon
  Bérard, Department of Medicine, Lyon, France
  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

2
Giant Cell Tumor of Bone (GCTB)

• Aggressive, primary osteolytic tumor
• Causes local pain and impairs mobility and
  function1
• No approved or effective medical therapy
• Surgical intervention often associated with
  significant morbidity2

1. Mendenhall WM et al. Am J Clin Oncol.
   200629969.
2. Balke M et al. J Cancer Res Clin Oncol.
   200913514958.

3
RANK and RANKL in Giant Cell Tumor of Bone

• Tumors contain osteoclast-like giant cells
  expressing RANK and stromal cells expressing RANK
  ligand (RANKL), a key mediator of osteoclast
  formation, activation, function, and survival.1-4
• Excessive RANKL secretion causes an imbalance in
  bone remodeling in favor of bone breakdown.5-7

RANK expression in GCTB8
1. Atkins GJ, et al. J Bone Miner Res. 2006
21133949. 2 Huang L, et al. Am J Pathol.
20001567617. 3. Kartsogiannis V, et al. Bone.
199925 52534. 4. Roux S, et al. Am J Clin
Pathol. 2002 1172106. 5. Burgess TL, et al. J
Cell Biol. 199914552738. 6 Lacey DL, et al.
Cell. 19989316576. 7. Yasuda H, et al. Proc
Natl Acad Sci USA. 1998953597602. 8. Bekker PJ
et al. J Bone Miner Res. 200419105966.
RANKL expression in GCTB8
4
RANKL is a Central Mediator of Bone Destruction
in Giant Cell Tumor of Bone
RANK
RANK
RANKL
RANKL
Osteoclast Precursors
Stromal Cellsof GCTB
5
Denosumab in Giant Cell Tumor of Bone

• Fully human monoclonal antibody that binds to
  RANKL1
• Inhibits osteoclast-mediated bone destruction
• Initial open-label, proof-of-concept, phase 2
  study of denosumab in GCTB (N 37)2
• Tumor response in 86 of patients with GCTB
• Clinical benefit in 84 of patients (reduced pain
  or improvement in functional status per
  investigator)
• No serious treatment-related adverse events

1. Bekker PJ et al. J Bone Miner Res.
   200419105966.
2. Thomas D et al. Lancet Oncol. 20101127580.

6
Phase 2 Follow-on Study Interim Analysis
Day
Month
1
8
15
2
3
4
5
Months 7 N
6
Denosumab 120 mg sc
Adults or skeletally mature adolescents with GCTB

• Cohort 2 Salvageable GCTB, surgery planned
• Safety
• Surgery delay, avoidance, or reduced morbidity

• Cohort 1 Surgically unsalvageable GCTB
• Safety
• Disease progression (investigators assessment)

SC subcutaneous
7
ResultsSubject Demographics and Disease
Characteristics
Characteristic (All enrolled subjects) Cohort 1 Surgically Unsalvageable N 112 Cohort 2 Salvageable, Surgery Planned N 50
Female , 63 58
Age, median (minmax) 32 (1376) 34 (1756)
Location of target lesion,
Femur, tibia, patella/knee, or tarsus 6 64
Lung 30 4
Sacrum 22 6
Pelvic bone 14 8
Humerus, radius, ulna, or metacarpus 5 12
Vertebrae cervical, thoracic, or lumbar 10 2
Skull 6 0
Soft tissue cervical, thoracic pelvic, or abdominal 4 4
N All enrolled subjects
8
Safety ResultsDenosumab Exposure and Adverse
Events
All Subjects N 158
Median (Q1Q3) number of doses received 10 (615)
Median (Q1Q3) months on study 7 (312)
Subjects with Adverse Events,
AEs of grade 3 or 4 considered related to denosumab 4.4
Hypophosphatemia 2.5
Dysmennorrhea 0.6
Osteonecrosis of the jaw (ONJ) 1.9
Hypocalcemia (grade 1 or 2) 4.4
N number of subjects who received at least 1
dose of denosumab
9
Efficacy Response per Investigator AssessmentNo
Disease Progression in the Majority of Subjects
Cohort 1 Surgically Unsalvageable N 73
Cohort 2 Salvageable, Surgery Planned N 23
38 (52)
1 (1)
2 (3)
N the number of subjects who received
denosumab, had the opportunity to be on study for
6 months, and had disease progression data at
the time of analysis. The disease response data
analysis was based on the best response reported
during the assessment period.
10
Efficacy Cohort 2At 12 Months, Most Subjects in
Cohort 2 Had No Surgery or a Less Morbid Surgical
Procedure Than Planned
Surgical Procedure, n Planned (N 23) Actual (N 23)
Total number of surgeries 23 8
Major surgeries 10 3
Hemipelvectomy 1 0
Amputation 2 0
Joint/prosthesis replacement 5 1
Joint resection 2 2
Marginal excision, en bloc excision, or en bloc resection 7 0
Curretage 2 4
Other 4 1
No surgery N/A 15
In order from most morbid to least morbid
Other planned skeletal procedures included
replacement of proximal tibia, sacral lesion/bone
resection, and pelvic resection (1 each).
11
Results Efficacy
36-year-old man with GCTB and severe pain, left
lower extremity
After 29 weeks of denosumab treatment
Baseline
12
Pre-Treatment (August 2009)
Courtesy of Alexander Fedenko, MD and Elke
Ahlmann, MD (USC)
13
Post-Treatment (Limb Salvage, September 2011)
Courtesy of Alexander Fedenko, MD and Elke
Ahlmann, MD (USC)
14
Summary

• Denosumab was well tolerated by these subjects
  with GCTB no new risks were observed in this
  population
• ONJ, a known risk with denosumab, was observed at
  a low rate consistent with that seen in other
  studies
• Disease progression was halted in 99 of subjects
• Of 23 subjects for whom surgery was planned
• 15 had no surgery
• 8 had less morbid surgeries than planned
• This study is ongoing denosumab continues to be
  studied as a potential treatment for GCTB