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

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.

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

1. Mendenhall WM, et al. Am J Clin Oncol. 2006;29:96-9. 2. Thomas DM, Skubitz KM. Curr Opin Oncol. 2009;21:338-344.

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;21:1339-1349.2. Huang L, et al. Am J Pathol. 2000;156:761-767.3. Roux S, et al. Am J Clin Pathol. 2002;117:210-21.6

4. Lau YS et al. Hum Pathol. 2005;36:945–54.5. Branstetter DG et al. Clin Cancer Res 2012; 8(16):4415-24.6. Bekker PJ, et al. J Bone Miner Res. 2004;19:1059-66.

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)

Study Design

1 8 15 2 3 4 5

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

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 Study10 Protocol-specific

criteria1 Adverse event2 Consent withdrawn2 Disease progression5 Other

81 on study at interim analysis cutoff date

100 analyzed for efficacy † 101 analyzed for safety †

Patients Enrolled: 282

21 Discontinued Study2 Complete tumor

resection7 Adverse event1 Consent withdrawn1 Disease progression2 Requirement for

alternative therapy1 Pregnancy7 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‡

Results: Baseline Demographics and Disease Characteristics

Characteristics(All enrolled patients), n (%)

Cohort 1Surgically

UnsalvageableN = 170

Cohort 2Salvageable,

Surgery PlannedN = 101

Cohort 3Patients from

Previous StudyN = 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) 57 (56) 1 (9)

Sacrum 42 (25) 4 (4) 2 (18)Lung 42 (25) 2 (2) 3 (27)Pelvic bone 23 (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)

Skull 7 (4) 0 (0) 0 (0)Pelvis (soft tissue only) 2 (1) 0 (0) 0 (0)Other 8 (5) 6 (6) 1 (9)

Results: GCTB Characteristics

Characteristics(All enrolled patients), n (%)

Cohort 1Surgically

UnsalvageableN = 170

Cohort 2Salvageable,

Surgery PlannedN = 101

Cohort 3Patients from

Previous StudyN = 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) 0 (0)

IV bisphosphonates 32 (19) 10 (10) 0 (0)Oral bisphosphonates 7 (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

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*)

Complete response

Partial response

Stable disease

Disease progression

0%

10%

20%

30%

40%

50%

60%

8 (5%)

57 (36%)

93 (58%)

1 (1%)

Complete response

Partial response

Stable disease

Disease progression

0%

10%

20%

30%

40%

50%

60%

17 (18%)

37 (40%) 38 (41%)

1 (1%)

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.

Clinical Benefit (Investigator-Determined)

N1 = number of enrolled patients who were eligible and received ≥ 1 dose of denosumab.

Pain reduc-

tion

Improved mobility

Improved function

Other0%

10%

20%

30%

40%

50%

60%

48 (28%)

38 (22%)32 (19%)

6 (4%)

Cohort 1: Surgically UnsalvageableN1 = 169*

Cohort 2: Salvageable, Surgery Planned

N1 = 100*

Pain reduc-

tion

Improved mobility

Improved function

Other0%

10%

20%

30%

40%

50%

60%

50 (50%)

33 (33%)

23 (23%)

10 (10%)

Best Response During the Assessment Period

Radiologic Response to Denosumab

Pre-Treatment Week 19 Post-Treatment

Radiologic Response to Denosumab

Baseline Week 5 Week 37

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 0

Amputation 17 0

Joint/prosthesis replacement 9 1

Joint resection 14 2

En bloc resection 37 6

En bloc excision 4 0

Marginal excision 1 0

Curettage 13 16

Other 1 1

No surgery 0 74

• 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

Adverse Events

Patients with Adverse Events, n* (%) All Patients

N = 281*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 3 (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

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