Giant cell tumor of bone (GCTB) is a progressive osteolytic tumor with proven response to denosumab when unresectable or at high surgical risk. We report on the primary analysis of this phase 2 study.
Patients (pts) were enrolled with unresectable GCTB (Cohort 1), resectable GCTB with planned high morbidity surgery (Cohort 2), and prior GCTB study pts (Cohort 3). Denosumab was given 120 mg SC every 4 weeks with loading doses on days 8 and 15. The primary endpoint was safety; efficacy endpoints included proportion of Cohort 2 pts without surgery, and progression-free survival for all pts.
Baseline characteristics and key safety results for 532 pts are shown in the Table. Median follow-up was 55 months (IQR 34, 75) in Cohort 1 and 44 months (IQR 26, 59) in Cohort 2. Overall response rates were 99% in Cohorts 1 and 2. Of 267 Cohort 1 pts, 19 (7%) ended denosumab for GCTB progression. Kaplan Meier (KM) estimates (95% CI) for GCTB progression in these pts were 4% (2–7%) at week 49, and 7% (4–10%) at week 98. 135 Cohort 1 pts ended denosumab without GCTB progression, and 34 (25%) recurred with a KM median estimate (95% CI) of 39 (18, NE) months. Of 248 Cohort 2 pts with planned surgery, 63% underwent surgery and 37% continued with denosumab only. Following surgery, 27% pts had a recurrence, higher after curettage than resection (34 vs 12%).
|N = 532 n (%)|
|Median age (range)||33 (13–83)|
|Adverse Events (AE)†||n = 526 All||Relatedb|
|Osteonecrosis of jawc||28 (5.3)||28 (5.3)|
|Serious AEs||138 (26.2)||42 (8.0)|
|Fatal AEs‡||10 (1.9)||2 (0.4)|
|AEs leading to study discontinuation||46 (8.7)||27 (5.1)|
Skeletally mature adolescents defined as age 12-17 years with radiographic evidence of at least 1 mature long bone with closed growth epiphyseal plate.†
Patients who received ≥1 dose of denosumab (safety analysis set)b
Considered by investigator to be possibly related to denosumabc
Positively adjudicated by two independent reviewers‡
Fatal AEs: Respiratory failure (2), Post radiation osteosarcoma* (1), Giant cell rich osteosarcoma (misdiagnosed)*b (1), Retroperitoneal leiomyosarcoma*b (1), Primary malignant GCTB (misdiagnosed)* (1), Renal cancer (1), Circulatory collapse (1), Completed suicide (1) [*Malignant cases reviewed by an external expert panel.]
Denosumab was generally well tolerated with excellent long-term disease control in unresectable patients. A 27% recurrence rate following surgery was seen in this high-risk, resectable population (26% had recurrent GCTB at enrollment). Adverse events were consistent with the known profile for denosumab, with no unexpected long-term toxicities. Several cases of misdiagnosed as benign GCTB at enrollment were seen, reinforcing the need for careful expert pathologic evaluation of this rare disease at diagnosis. Denosumab has major, long-lasting antitumor activity in unresectable or metastatic GCTB.
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Legal entity responsible for the study
E. Palmerini: Amgen advisory board. J-Y. Blay: Research grants from Novartis, Roche, Pharmamar, Bayer, Ignyta, GSK, Lilly and Amgen, and has served as a consultant for Novartis, Roche, Pharmamar, Bayer, Ignyta, GSK, Lilly and Amgen A. Le Cesne: Consulting fees from Novartis, Pfizer, Lilly and Pharmamar. P. Reichardt: Advisory boards for Novartis, Pfizer, Bayer, PharmaMar, Ariad, Amgen, Inc., GlaxoSmithKline, AstraZeneca, Clinigen, and Lilly, and has received honoraria from Novartis, Pfizer, Bayer, PharmaMar, Amgen, Inc., GlaxoSmithKline, and Lilly. P. Rutkowski: Consultant for Amgen, MSD, BMS, Novartis and Roche and served on speaker’s bureaus for Novartis, Pfizer, BMS, MSD and Roche, and advisory board for Blueprint. H. Gelderblom: Institution has received grants and consultancy fees from Amgen. R.J. Grimer: Scientific advisory board for Amgen for this trial. A. Feng: Employee of Amgen during the time that this abstract was written. D. Jandial: Employee and Stockholder of Amgen. S. Chawla: Advisor and consultant for Amgen.