A phase II study has found that denosumab was able to halt progression in the vast majority of enrolled patients with giant cell tumor of the bone as well as reducing the need for surgery.
Sean E. Harper, MD
A phase II study has found that the monoclonal antibody denosumab (Xgeva) was able to halt progression of the disease in the vast majority of enrolled patients with giant cell tumor of the bone (GCTB) as well as reducing the need for surgery that could put the patients at further risk for complications.
The results of the trial were published in the online edition of the journal Lancet Oncology.
GCTB is a relatively rare disease that is diagnosed in approximately 300-800 patients annually in the United States. It is a locally aggressive, benign tumor that typically affects the methaepiphysis of long bones, and in rare cases, patients develop pulmonary metastases.
Denosumab is a RANK ligand antibody that has been shown to significantly reduce the number of RANK-positive giant cells and proliferative stromal cells. In 2010, the FDA approved denosumab for prevention of skeletal-related events in patients with bone metastases from solid tumors. In 2011, the drug was approved to increase bone mass in patients who are at high risk of fracture from receiving androgen deprivation therapy for nonmetastatic prostate cancer or adjuvant aromatase inhibitor therapy for breast cancer. In June, the FDA also approved denosumab for the treatment of adults and skeletally mature adolescents with GCTB that is unresectable or where surgical resection is likely to result in severe morbidity. This phase II study confirms the effectiveness in this intended treatment population.
This international, open-label, parallel-group, phase II trial, enrolled 282 patients with histologically confirmed GCTB and radiographically measurable active disease. Patients were divided 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 the first two cohorts received 120 mg of subcutaneous denosumab every 4 weeks with loading doses on days 8 and 15 of the first cycle, whereas those in the third cohort continued their regimens from the previous study. The primary endpoint of this study was the safety profile, with secondary endpoints varying by cohort and including time to disease progression and the proportion of patients without any surgery at 6 months.
In the first cohort, 163 of 169 (96%) analyzable patients had no disease progression after median follow-up of 13 months (Interquartile Range [IQR], 5.8-21.0). In the second cohort, 74 of 100 (74%) analyzable patients had no surgery and 16 of 26 (62%) patients who received surgery underwent a less morbid procedure than what had been originally planned. The median follow-up in this cohort was 9.2 months (IQR, 4.2-12.9).
Treatment-related adverse events were consistent with the established safety profile of denosumab. Among the 281 patients who were analyzable for safety, three patients had osteonecrosis of the jaw and 15 patients experienced hypocalcaemia. The most common grade 3 or 4 events were hypophosphataemia (3%), anemia (1%), back pain (1%), and pain in extremities (1%). A total of 25 patients (9%) reported serious adverse events, and no treatment-related deaths were observed.
“These results demonstrate the effectiveness of Xgeva in the treatment of giant cell tumor of bone and reinforce our understanding of this rare disease in which RANK Ligand plays a central role,” said Sean E. Harper, MD, executive vice president of Research and Development at Amgen, in a statement. “Xgeva represents a much-needed treatment option for patients who suffer from giant cell tumor of bone that can't be adequately treated with surgery.”
Chawla S, Henshaw R, Seeger L, et al. Safety and efficacy of denosumab for adults and skeletally mature adolescents with giant cell tumor of the bone: interim analysis of open-label, parallel-group, phase 2 study [published online ahead of print July 16, 2013]. Lancet Oncol. doi: doi:10.1016/S1470-2045(13)70277-8.