Presentation on theme: "Safety and Efficacy of Denosumab for Giant Cell Tumor of Bone"— Presentation transcript:
1Safety 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 Jacobs131University 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
2Acknowledgements 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.
3Giant Cell Tumor of Bone (GCTB) Locally aggressive, destructive primary bone tumorCauses pain and swelling and impairs mobility and function1No standard or approved medicinal therapySurgical intervention often associated with significant morbidity2Mendenhall WM, et al. Am J Clin Oncol. 2006;29:96-9.Thomas DM, Skubitz KM. Curr Opin Oncol. 2009;21:
4Denosumab in GCTBGCTB 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.1-6High levels of RANKL also stimulate giant cell activation and survival and tumor-induced bone lysis.3-5Denosumab is a fully human monoclonal antibody against RANKL.6Denosumab inhibits bone destruction by preventing RANKL-mediated formation, activation, and survival of osteoclast-like giant cells.5Atkins GJ, et al.. J Bone Miner Res. 2006;21:Huang L, et al. Am J Pathol. 2000;156:Roux S, et al. Am J Clin Pathol. 2002;117:Lau YS et al. Hum Pathol. 2005;36:945–54.Branstetter DG et al. Clin Cancer Res 2012; 8(16):Bekker PJ, et al. J Bone Miner Res. 2004;19:
5ObjectivesTo evaluate the safety profile of denosumab in patients with GCTB treated with denosumabTo evaluate time to disease progression in patients with unsalvageable GCTBTo 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 surgeryThis 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)
6Adults or skeletally mature adolescents with GCTB Study Design181523456Months 7 to NDenosumab 120 mg SCAdults or skeletally mature adolescents with GCTBCohort 1: Surgically unsalvageable GCTBCohort 2: Salvageable GCTB with planned surgeryCohort 3*: Patients who transitioned from previous denosumab GCTB studyPrimary EndpointSafety profile of denosumabKey Secondary EndpointsCohort 1: Time to disease progressionCohort 2: Proportion of patients without any surgery at month 6*No loading doses on days 8 and 15N = number of months on study
7Results: Study Participation Patients Enrolled: 282Cohort 3: 11 patients0 Discontinued Study11 on study at interim analysis cutoff date11 analyzed for efficacy ‡ 11 analyzed for safety‡Cohort 1: 170 patientsCohort 2: 101 patients21 Discontinued Study2 Complete tumor resection7 Adverse event1 Consent withdrawn1 Disease progression2 Requirement for alternative therapy1 Pregnancy7 Other20 Discontinued Study10 Protocol-specific criteria1 Adverse event2 Consent withdrawn2 Disease progression5 Other149 on study at interim analysis cutoff date81 on study at interim analysis cutoff date169 analyzed for efficacy * 169 analyzed for safety *100 analyzed for efficacy † 101 analyzed for safety †*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.
8Results: Baseline Demographics and Disease Characteristics (All enrolled patients), n (%)Cohort 1Surgically UnsalvageableN = 170Cohort 2Salvageable, Surgery PlannedN = 101Cohort 3Patients from Previous StudyN = 11Female102 (60)57 (56)5 (45)Age, median (min–max)33 (13–83)34 (16–69)30 (22–63)Location of target lesionFemur, tibia, fibula, or patella/knee14 (8)1 (9)Sacrum42 (25)4 (4)2 (18)Lung2 (2)3 (27)Pelvic bone23 (14)12 (12)0 (0)Humerus, radius, ulna, or metacarpus11 (6)17 (17)Vertebrae: cervical, thoracic, or lumbar21 (12)3 (3)Skull7 (4)Pelvis (soft tissue only)2 (1)Other8 (5)6 (6)
9Results: GCTB Characteristics (All enrolled patients), n (%)Cohort 1Surgically UnsalvageableN = 170Cohort 2Salvageable, Surgery PlannedN = 101Cohort 3Patients from Previous StudyN = 11GCTB disease typePrimary48 (28)63 (62)2 (18)Recurrent122 (72)38 (38)9 (82)Prior GCTB therapiesSurgery130 (76)44 (44)UnknownRadiation42 (25)6 (6)0 (0)Chemo/Immunotherapy24 (14)2 (2)IV bisphosphonates32 (19)10 (10)Oral bisphosphonates7 (4)1 (1)IV: intravenousThe median number of doses was 13 (range, 1-33).The median time on study was 10 months (range, 0-29).
10Disease Status (Investigator-Determined) Best Response During the Assessment PeriodCohort 1: Surgically Unsalvageable (N1 = 159*)Cohort 2: Salvageable, Surgery Planned (N1 = 93*)N1 = number of enrolled patients who were eligible and received ≥ 1 dose of denosumab and had a disease status evaluation.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.
11Clinical Benefit (Investigator-Determined) Best Response During the Assessment PeriodCohort 1: Surgically UnsalvageableN1 = 169*Cohort 2: Salvageable, Surgery PlannedN1 = 100*N1 = number of enrolled patients who were eligible and received ≥ 1 dose of denosumab.
12Radiologic Response to Denosumab Pre-TreatmentWeek 19 Post-TreatmentThese are CT scans of the left distal femur before and after treatment.
13Radiologic Response to Denosumab BaselineWeek 5Week 37These are CT scans of the lung before and after treatment.Post-treatment CT scans showed reductions in the size of the nodule in the right lower lobe (arrow).
14Planned Versus Actual Surgery in Cohort 2 Surgical Procedure, n* (In decreasing order of morbidity)Baseline Planned (N =100)Actual Total (N = 26)All surgeries10026Major surgeries443Hemipelvectomy4Amputation17Joint/prosthesis replacement91Joint resection142En bloc resection376En bloc excisionMarginal excisionCurettage1316OtherNo surgery74* n = number of patientsOf 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.
15Adverse Events Patients with Adverse Events, n* (%) All Patients Any adverse event236 (84)Adverse events occurring with > 10% frequencyArthralgia55 (20)Headache51 (18)Nausea48 (17)Fatigue45 (16)Back pain42 (15)Pain in extremity41 (15)Grade 3,4, or 5 adverse events50 (18)Serious adverse events25 (9)Adverse events leading to treatment discontinuation14 (5)Adverse event of interestAdjudicated positive ONJ3 (1)Resolved†2 (1)Hypocalcemia (none serious)15 (5)Serious infections5 (2)New primary malignancyBased 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
16SummaryThe safety profile of denosumab in these patients with GCTB was consistent with that observed in other denosumab trials; no new risks were observedONJ and hypocalcemia, known risks of denosumab, were observed at a low rate consistent with that seen in other studies96% of Cohort 1 patients had no disease progression at any time on study, as determined by the investigatorOf 100 patients for whom surgery was planned:74 had no surgery16 of 26 had less morbid surgeries than plannedDenosumab 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