ArticlesSafety and efficacy of denosumab for adults and skeletally mature adolescents with giant cell tumour of bone: interim analysis of an open-label, parallel-group, phase 2 study
Introduction
Giant cell tumour of bone (GCTB) is a rare, osteolytic tumour that mainly occurs in young adults (peak incidence is in the third and fourth decades).1, 2 Although deemed histologically benign, it is locally aggressive and destroys bone and overlying soft tissue. Metastatic spread or implants from the primary tumour occur in as much as 6% of patients, most frequently in the pulmonary parenchyma.1, 3, 4 GCTB can cause substantial morbidity because of its predilection for bones surrounding the knee joint or wrist and can occur in the axial skeleton.2
Surgery is the preferred treatment and can be curative if adequate resection is possible,5, 6 although local recurrence or metastasis can still occur. Without adequate resection, rates of tumour recurrence are high.7 However, aggressive surgical approaches that aim to reduce the risk of recurrence are often associated with significant morbidity (eg, joint resection, joint replacements or prostheses, amputation, hemipelvectomy).7 For patients with unresectable GCTB, radiotherapy and serial embolisation provide palliation from symptoms, but durable responses are uncommon, and malignant transformation can occur after radiation. No approved or standard systemic treatment exists. Use of chemotherapeutics, bisphosphonates, or other drugs has been reported,7, 8, 9 but none of these drugs provided consistent sustained responses.
The pathophysiology of GCTB is amenable to targeted therapy, because, in giant cell tumours, neoplastic stromal cells express high concentrations of RANK ligand (RANKL) and activate RANK-positive osteoclast-like giant cells and their precursors.7, 10, 11, 12, 13, 14, 15 Denosumab is a fully human monoclonal antibody that inhibits RANKL, thereby preventing RANK–RANKL interactions and GCTB-induced bone destruction.13, 16, 17 Results from a phase 2 study18 of denosumab showed a tumour response in 30 of 35 patients with GCTB.18 In a larger subsequent phase 2 study, we now report the safety and efficacy of denosumab in adults and skeletally mature adolescent patients with GCTB who had surgically salvageable or unsalvageable disease. We also report, for the first time, results from a systematic, independent imaging assessment of the response of GCTB to denosumab.
Section snippets
Patients and procedures
Our study was an open-label, parallel-group, phase 2 trial at 29 centres in North America, Europe, and Australia between Sept 9, 2008, and March 25, 2011 (the cutoff for data analysis). We did the first interim analysis (prespecified) when 50 patients were projected to have completed 6 months of treatment. Subsequent interim analyses were planned after 100 patients were projected to have completed 6 months of treatment. For the interim analysis described here, we expected that more than 200
Results
We enrolled 282 patients (170 in cohort 1, 101 in cohort 2, and 11 in cohort 3), including ten adolescents (eight in cohort 1 and two in cohort 2). 41 (15%) patients discontinued the study before the analysis cutoff, most frequently because they underwent complete tumour resection, as specified by the protocol. Two patients in cohort 1 underwent surgery with curative intent (judged to be complete resection) after denosumab therapy. Two adolescent patients discontinued the study (one was lost to
Discussion
Adverse events were consistent with the known safety profile of denosumab, and only 5% of patients discontinued because of toxic effects (panel). Hypocalcaemia and osteonecrosis (known risks associated with denosumab) were reported but rare. None of the adolescents enrolled in the study had a serious adverse event. Nearly all patients with surgically unsalvageable GCTB had no disease progression as determined by investigators. Similarly, most patients with either surgically salvageable or
References (25)
- et al.
Clinicopathologic profile of 470 giant cell tumors of bone from a cancer hospital in western India
Ann Diagn Pathol
(2008) - et al.
Benign bone tumors—recent developments
Semin Diagn Pathol
(2011) - et al.
Gene expression of osteoprotegerin ligand, osteoprotegerin, and receptor activator of NF-kappaB in giant cell tumor of bone: possible involvement in tumor cell-induced osteoclast-like cell formation
Am J Pathol
(2000) - et al.
Gene expression in giant-cell tumors
J Lab Clin Med
(2004) - et al.
Recruitment of osteoclast precursors by stromal cell derived factor-1 (SDF-1) in giant cell tumor of bone
J Orthop Res
(2005) - et al.
Phenotypic and molecular studies of giant-cell tumors of bone and soft tissue
Hum Pathol
(2005) - et al.
Denosumab in patients with giant-cell tumour of bone: an open-label, phase 2 study
Lancet Oncol
(2010) - et al.
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1·1)
Eur J Cancer
(2009) - et al.
Measurement of clinical and subclinical tumour response using [18F]-fluorodeoxyglucose and positron emission tomography: review and 1999 EORTC recommendations
Eur J Cancer
(1999) - et al.
Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study
Lancet
(2011)
Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials
Eur J Cancer
Giant cell tumor of bone
Am J Clin Oncol
Cited by (452)
Histological and immunohistochemical analyses of osteoclast maturation in giant cell tumor of bone
2024, Pathology Research and PracticeMalignant transformation of metastatic giant cell tumor of bone in a patient undergoing denosumab treatment: A case report
2023, Journal of Orthopaedic ScienceThe Role of Denosumab in the Treatment of Primary Tumors of Bone
2023, Journal of Hand SurgeryGenetic characterization of a novel organoid from human malignant giant-cell tumor
2023, Journal of Bone Oncology