As reported by Chawla et al in The Lancet Oncology, long-term data from the final analysis of an international phase II study suggest that a favorable risk-benefit ratio is maintained over time with denosumab treatment of patients with giant cell tumor of bone. Benefit of denosumab was indicated in interim analysis in the trial, reported in 2013.

Study Details    

The study included 532 patients enrolled between September 2008 and February 2016 from 30 sites in 12 countries who had had surgically unsalvageable giant cell tumor of bone (cohort 1, n = 267), surgically salvageable disease with planned surgery expected to result in severe morbidity (cohort 2, n = 253), and patients enrolled from a prior study of denosumab in giant cell tumor of bone (cohort 3, n = 12).

Patients received subcutaneous denosumab at 120 mg once every 4 weeks, with loading doses of 120 mg given on study days 8 and 15 to patients in cohorts 1 and 2. Patients in cohort 2 with complete resection received adjuvant denosumab for six doses after confirmation of partial or complete response. All other patients continued treatment until disease progression; discontinuation by investigator, sponsor, or patient decision; absence of clinical benefit; or other protocol-specified reason. 

The primary endpoint was safety analyzed by type, frequency, and severity of adverse events; secondary endpoints included time to disease progression in cohort 1 and proportion of patients without surgery at month 6 in cohort 2.

Adverse Events

Median follow-up was 58.1 months. During treatment, the most common grade ≥ 3 adverse events were hypophosphatemia (5%), osteonecrosis of the jaw (3%), pain in extremity (2%), and anemia (2%). Serious adverse events were reported in 26% of patients, with the most common being osteonecrosis of the jaw (3%), anemia (1%), bone giant cell tumor (1%), and back pain (1%).

Overall, 28 patients (5%) had positively adjudicated osteonecrosis of the jaw, 4 (1%) had atypical femur fracture, and 4 (1%) had hypercalcemia within 30 days after denosumab discontinuation. Sarcomatous transformation occurred in four patients (1%). Two deaths were considered related to treatment, due to bone sarcoma in a patient in cohort 2 and sarcoma in a patient in cohort 1.

Efficacy Outcomes

Among 509 patients in cohorts 1 and 2 evaluable for response, clinical benefit was observed in 507 (99%), including complete response in 37%, partial response in 34%, and stable disease in 29%. Median time to progression or recurrence in cohort 1 was not reached, with progression or recurrence being observed in 28 (11%) of 262 patients. No surgery was performed during the first 6 months of the study in 227 (92%) of 248 patients in cohort 2.

The investigators concluded, “The types and frequencies of adverse events were consistent with the known safety profile of denosumab, which showed long-term disease control for patients with giant cell tumor of bone with unresectable and resectable tumours. Our results suggest that the overall risk to benefit ratio for denosumab treatment in patients with giant cell tumor of bone remains favorable.”

Emanuela Palmerini, MD, of IRCCS Istituto Ortopedico Rizzoli/Department of Experimental, Diagnostic and Specialty Medicine, Università di Bologna, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Amgen. For full disclosures of the study authors, visit thelancet.com.