Abstract #10034

1. 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

2. BACKGROUND • 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

3. Figure 1. RANKL is a Central Mediator of the Vicious Cycle of Bone Destruction in GCTB

4. 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.

5. Figure 2. Denosumab May Interrupt the Vicious Cycle of GCTB-induced Bone Destruction

6. 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

7. 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

8. 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

9. RESULTS Table 1. Subject Disposition and Denosumab Exposure • 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.

10. Table 2. Subject Demographics * Includes all enrolled subjects

11. Table 3. Subject Disease Characteristics * Includes all enrolled subjects † In order of frequency; data missing for 1 subject

12. SafetyTable 4. Adverse Events * 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.

13. 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.

14. EfficacyFigure 4. No Disease Progression in the Majority of Subjects Cohort 1 Surgically unsalvageable N = 73* Cohort 2Salvageable, surgery planned N = 23* * 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.

15. 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).

16. Table 5. Most Cohort 2 Subjects Had No Surgery or a Less Morbid Surgical Procedure Than Planned * 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.

17. Summary • This interim analysis describes 158 adult and adolescent subjects with GCTB who received treatment with denosumab of an open-label 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.

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19. 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.