1. Assessment of Surgical Downstaging in an Open-Label Phase 2 Trial of Denosumab in Patients With Giant Cell Tumor of Bone Piotr Rutkowski, 1 Stefano Ferrari, 2 Robert J. Grimer, 3 Paul D. Stalley, 4 Sander P. D. Dijkstra, 5 Andrzej Pienkowski, 1 Gualter Vaz, 6 Leanne L. Seeger, 7 Amy Feng, 8 Bruce A. Bach 9 1 Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Memorial Center and Institute of Oncology, Warsaw, Poland; 2 Chemotherapy Unit, Istituto Ortopedico Rizzoli, Bologna, Italy; 3 Orthopaedic Oncology Unit, Royal Orthopaedic Hospital, Birmingham, UK; 4 Department of Orthopaedic Surgery, Royal Prince Alfred Hospital, Sydney, NSW, Australia; 5 Department of Orthopedic Surgery, Leiden University Medical Center, Leiden, Netherlands; 6 Department of Orthopedic Surgery, Edouard Herriot Hospital, Lyon, France; 7 Department of Radiology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA, USA; 8 Global Biostatistical Science, Amgen Inc., Thousand Oaks, CA, USA; 9 Global Development Oncology Therapeutics, Amgen Inc., Thousand Oaks, CA, USA

2. 2 Disclosures P Rutkowski, LL Seeger: honoraria (Amgen Inc.) S Ferrari: advisory boards (Amgen Inc., GlaxoSmithKline); research funding (MolMed, Pharmar, Morphotek, Amgen Inc.); honoraria (Takeda) RJ Grimer: advisory board (Amgen Inc.) SPD Dijkstra: advisory board (Implantcast GmbH) A Feng, BA Bach: employment and stock ownership (Amgen Inc.) PD Stalley, A Pienkowski, G Vaz: no disclosures

3. 3 Giant cell tumor of bone (GCTB) lesions are typically histologically benign and composed of multinuclear osteoclast-like giant cells expressing surface RANK and mononuclear stromal cells expressing RANK ligand (RANKL) 1 Denosumab is a fully human monoclonal antibody that inhibits RANKL 2 RANK ExpressionRANKL Expression Mononuclear stromal cells Multinuclear giant cells Targeting RANKL in GCTB 1. Branstetter D, et al. Clin Cancer Res. 2012;18:4415-4424 2. Bekker PJ, et al. J Bone Miner Res. 2004;19:1059-1066

4. 4 Design Phase 2 Trial (20062004) 18152345 Denosumab 120 mg SC DayMonth Months 7 to N Cohort 2 : Salvageable GCTB with planned surgery Safety Disease progression Disease status and clinical benefit Surgery: delay, avoidance, or reduced morbidity Cohort 1 : Surgically unsalvageable GCTB Safety Disease progression Disease status and clinical benefit 6 Adults or skeletally mature adolescents with GCTB SC = subcutaneous loading doses on days 8 and 15 of cycle 1 Serial clinical and radiologic evaluation Loading dose

5. 5 Baseline Demographics, Disease Characteristics, and Exposure in Cohort 2 Exposure to denosumab in cohort 2 (N = 222) Median (IQR) time on denosumab: 14.1 months (11.2–23.0) Median (IQR) doses: 18.0 (14.0–27.0) Exposure to denosumab in patients for whom surgery has not yet occurred (n = 106) Median (IQR) time on denosumab: 18.4 months (12.1–28.6) Median (IQR) doses: 22.5 (15.0–34.0) a Median age, 34 y (IQR, 25–44)

6. 6 Location of GCTB Lesion at Baseline N = 222/106 Baseline, treated/patients who did not undergo surgery Humerus 16/7 Femur 45/20 Tibia 62/27 Skull 1/1 Hyoid 1/0 Scapula 1/1 Radius 32/13 Fibula 5/1 Calcaneus 3/2 Talus 2/1 Phalanx (first finger) 2/1 Lumbar vertebrae 4/3 Sacrum 13/9 Ulna 5/3 Thoracic vertebrae 4/2 Pelvis (incl. ilium, ischium) 20/11 ≥ 50% lesions remain on treatment where initial n > 2 Midhand (metacarpal, carpal) 6/4

7. 7 Planned Versus Actual Surgery (N = 222) Actual On-Study Procedure Planned Procedure No Surgery (n = 106) Curettage (n = 80) Marginal Excision (n = 3) En Bloc Excision (n = 1) En Bloc Resection (n = 20) Joint Resection/ Fusion (n = 5) Joint/ Prosthesis Replacement (n = 6) Amputation (n = 1) Hemi- pelvectomy (n = 0) Hemipelvectomy (n = 10) 81––––1–– Amputation (n = 40) 3232–––3–– Joint/prosthesis replacement (n = 25) 616–11–1–– Joint resection/ fusion (n = 35) 14 ––25––– En bloc resection (n = 85) 31391–13–1–– En bloc excision (n = 8) 7–––1–––– Marginal excision (n = 1) –––––––1– Curettage (n = 18) 87––3–––– In total, 190 (86%) patients had either no surgery (n = 106; 48%) or surgery associated with less morbidity (n = 84; 38%) No surgeryMore morbidPlanned procedureLess morbid

8. 8 Planned Versus Actual Curative-Intent Surgery (N = 222) Proportions of patients with a planned surgical procedure who had not yet undergone surgery with curative intent: –Hemipelvectomy (80%) –Amputation (80%) –Joint/prosthesis replacement (24%) –Joint resection/fusion (40%) –En bloc resection (36%) –En bloc excision (88%) –Curettage (44%) Native joint preservation rate: −96% in 25 patients with a planned joint/prosthesis replacement −86% in 35 patients with a planned joint resection/fusion 6 (3%) 26 (12%) 84 (38%) 106 (48%)

9. 9 Radiologic Appearance of GCTB of Proximal Radius (Pre- and Post-denosumab) A, B: Radiographs of a large, expansile, completely osteolytic lesion in the proximal radius demonstrating a permeative destruction pattern with cortical destruction, consistent with GCTB. C, D: Radiographs demonstrate new bone formation with reconstitution of cortical bone after 5 months of treatment with denosumab. Reproduced with permission from van der Heijden et al. Oncologist. 2014;19:550-561. Pre-denosumab Post-denosumab

10. 10 GCTB of the proximal humerus. The initial lesion (A) was expansile with a thin peripheral calcified shell and primarily soft tissue density centrally. After 4 months of treatment with denosumab (B), the peripheral calcification was thicker, the central lesion more heavily mineralized, and the overall size slightly decreased Response to Denosumab in GCTB of Proximal Humerus Pre-denosumab Post-denosumab

11. 11 Response to Denosumab and Surgery in Locally Advanced GCTB of Distal Femur Locally advanced GCTB of the distal femur in a 38-year-old patient with planned amputation. (A) Initial tumor with extensive soft tissue infiltration with progression after radiotherapy for previous 2 years. (B) Response to denosumab therapy with tumor calcification. (C) R0 tumor resection with implantation of oncological prosthesis (surgical treatment after 22 months of treatment) – further therapy with denosumab was stopped; CR 10/2014. A BC Pre-denosumab Post-denosumab

12. 12 Adverse Events Patients With Adverse Events, n (%) Cohort N = 222 Overall safety summary193 (87) Adverse events occurring with > 10% frequency Arthralgia55 (25) Fatigue46 (21) Pain in extremity43 (19) Headache42 (19) Nausea40 (18) Back pain24 (11) Grade 3 or 4 adverse events33 (15) Hypophosphatemia a 6 (3) Pain in extremity a 3 (1) Serious adverse events21 (10) Adverse events leading to treatment discontinuation9 (4) Adverse events of interest Hypocalcemia (none serious)7 (3) Serious infections6 (3) New primary malignancy b 4 (2) Adjudicated positive osteonecrosis of the jaw1 (< 1) Resolved c 1 (< 1) Based on Medical Dictionary for Regulatory Activities, version 14.1, and Common Terminology Criteria for Adverse Events, version 3.0 a Hypophosphatemia and pain in extremity were the only grade 3 or 4 adverse events occurring with a frequency ≥ 1% b Four patients were reported with malignant GCTB transformation on study: two in field radiation–associated sarcomatous transformation at 4 and 6 years postradiotherapy; two patients with pelvic or sacral GCTB lesions sampled via needle biopsy at the original diagnosis progressed on denosumab by 257 days of exposure—retrospective attribution by investigator to be primary malignant GCTB at original presentation missed on core needle biopsy c One case resolved (index condition no longer present) by the cutoff date

13. 13 Summary Of the 222 patients with resectable GCTB and a planned resection who enrolled and received denosumab, 86% derived clinical benefit –106 patients (48%) avoided any surgery –84 patients (38%) had a less morbid surgical procedure The native joint preservation rate was –96% in the 25 patients with planned joint/prosthesis replacement –86% in the 35 patients with a planned joint resection/fusion Denosumab was well tolerated in this population of patients with GCTB; no new safety risks were observed −Osteonecrosis of the jaw and hypocalcemia were observed at low rates, consistent with previous studies of denosumab