Elsevier

The Lancet Oncology

Volume 14, Issue 9, August 2013, Pages 901-908
The Lancet Oncology

Articles
Safety 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

https://doi.org/10.1016/S1470-2045(13)70277-8Get rights and content

Summary

Background

Giant cell tumour of bone (GCTB) is a very rare, aggressive, and progressive osteolytic tumour for which no standard medicinal treatment or chemotherapy exists. We report interim safety and efficacy results from a phase 2 study of denosumab in patients with GCTB.

Methods

We did an international, open-label, parallel-group, phase 2 trial of patients with histologically confirmed GCTB and radiographically measurable active disease. Eligible patients were adults or skeletally mature adolescents with radiographic evidence of at least one mature long bone who were at least 12 years old and weighed at least 45 kg. We divided patients into three cohorts—those with surgically unsalvageable GCTB (cohort 1), those with salvageable GCTB whose surgery was associated with severe morbidity (cohort 2), and those who transferred from a previous study of denosumab for GCTB (cohort 3). Patients in cohorts 1 and 2 received 120 mg of subcutaneous denosumab every 4 weeks with loading doses on days 8 and 15 of the first cycle; those in cohort 3 continued the regimen from the previous study. Investigator-determined disease status and clinical benefit were assessed every 4 weeks. Our primary endpoint was the safety profile of denosumab in terms of adverse events and laboratory abnormalities. Prespecified secondary endpoints were time to disease progression in cohort 1 and the proportion of patients without any surgery at 6 months in cohort 2. Safety analyses included all patients who received at least one dose of denosumab. Efficacy analyses included all eligible patients who received at least one dose of denosumab. This study is registered with ClinicalTrials.gov, identifier NCT00680992.

Findings

282 patients, including ten adolescents, were included between Sept 9, 2008, and March 25, 2011. Of the 281 patients analysable for safety, three (1%) had osteonecrosis of the jaw and 15 (5%) hypocalcaemia. The most common grade 3–4 adverse events were hypophosphataemia, which occurred in nine (3%) patients, and anaemia, back pain, and pain in extremities, each of which occurred in three patients (1%). Serious adverse events were reported in 25 (9%) patients. No treatment-related deaths were reported. On the basis of investigators' assessment of disease status, 163 of 169 (96%) analysable patients in cohort 1 had no disease progression after median follow-up of 13 months (IQR 5·8–21·0). In cohort 2, 74 of 100 (74%) analysable patients had no surgery and 16 of 26 (62%) patients who had surgery underwent a less morbid procedure than planned. Median follow-up in cohort 2 was 9·2 months (IQR 4·2–12·9).

Interpretation

Adverse events were consistent with the known safety profile of denosumab. Denosumab was associated with tumour responses and reduced the need for morbid surgery in patients with GCTB. Denosumab represents a new treatment option for patients with GCTB.

Funding

Amgen.

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)

  • A Lipton et al.

    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

    (2012)
  • WM Mendenhall et al.

    Giant cell tumor of bone

    Am J Clin Oncol

    (2006)
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