By Charles Bankhead, Staff Writer, MedPage Today
Published: December 03, 2011
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco.
CHICAGO — Giant cell tumor of bone exhibited near-total absence of disease progression during treatment with denosumab (Xgeva), results of an ongoing international trial showed.
All but one of 96 patients had stable disease or better response to treatment with the RANK ligand inhibitor, including objective responses in almost half of the patients.
In a subgroup of 23 patients with surgically salvageable disease, 15 avoided surgery and five others had less extensive surgery than originally planned.
Denosumab was generally well tolerated, and no unexpected adverse events occurred, investigators reported here at the International Conference on Cancer-Induced Bone Disease.
“Disease progression was halted in 99% of subjects,” Sant Chawla, MD, of the Sarcoma Oncology Center in Santa Monica, Calif., and colleagues noted in their poster presentation.
Giant cell tumor of bone is a rare but aggressive osteolytic cancer that causes substantial skeletal morbidity. Typically affecting young adults, the malignancy grows rapidly and spreads into surrounding soft tissues.
Surgery remains the only definitive therapy, but a majority of patients have unresectable tumors at presentation, Chawla and colleagues noted. When surgery is feasible, procedures tend to be extensive and associated with significant morbidity.
No systemic therapy has been approved for use in giant cell tumor of bone.
Osteoclast-like tumor cells express receptor activator of nuclear factor kappa-B (RANK), and the tumor contains stromal cells that express RANK ligand, a mediator of osteoclast formation.
The resulting imbalance in bone remodeling in favor of resorption provided a rationale for evaluating denosumab in giant cell tumor of bone.
The investigators — at facilities in North America, Europe, and Australia — enrolled adults or adolescents with mature skeletal structure. Patients received denosumab by subcutaneous injection on days one, eight, and 15, and then once every four weeks until disease progression or development of unacceptable adverse events.
The primary outcomes for patients with surgically unsalvageable disease (unresectable or metastatic) were safety and disease progression during denosumab treatment.
For patients with surgically salvageable disease, outcomes also included changes in planned surgery after treatment with denosumab. Surgery could occur at any time while a patient was on study, according to the surgeon’s clinical judgment.
Patients who underwent surgery that ended with incomplete tumor resection could continue treatment with denosumab at the clinical investigator’s discretion.
Chawla and colleagues reported interim data for 73 patients with unresectable disease and 23 with resectable tumors, all of whom had received denosumab for a minimum of six months. That patient population provided the basis for the efficacy analysis. Safety data came from 158 patients who have been enrolled in the study thus far.
Women accounted for about 60% of the patients, who had a median age of about 33. Age of the patients ranged from 13 to 76. Among patients with surgically resectable tumors, the primary location was the femur, tibia, patella/knee, or tarsus in two-thirds of cases.
The most commonly reported adverse events during denosumab treatment were fatigue, back pain, headache, pain in the extremity, arthralgia, and nausea, occurring in 11% to 15% of patients. Seven patients (4%) developed hypocalcemia, a known risk of treatment with denosumab.
Three (1.9%) developed osteonecrosis of the jaw, also a known risk with denosumab. All three patients had a history of tooth extraction or suboptimal dental hygiene. The time to onset of osteonecrosis of the jaw ranged from 12.5 to 20.3 months.
Efficacy results for the 73 patients with surgically unsalvageable disease showed that two patients (3%) had a complete response and 32 (44%) had a partial response. An additional 38 patients (52%) had stable disease, and one had disease progression.
In the cohort with surgically salvageable tumors, five (22%) had complete responses, seven (30%) had partial responses, and the remaining 11 had stable disease. No tumors progressed during treatment with denosumab by investigator assessment.
Three patients had major surgery as originally planned: one joint/prosthesis replacement (of five originally planned) and two joint resections, both of which had been planned.
The study was supported by Amgen, manufacturer of denosumab.
Chawla disclosed relationships with Amgen, Ariad, Merck, Ziopharm Oncology, and Epeius Biotechnologies. Other investigators disclosed relationships with Pfizer, Novartis, GlaxoSmithKline, Roche, PharmaMar, Imclone Systems, Keryx Biopharmaceuticals, Johnson & Johnson, Celgene, Cell Therapeutics, Daiichi Sankyo, SMI, Schering-Plough, and Bayer. Investigators included employees of Amgen.
Primary source: International Conference on Cancer-Induced Bone Disease
Chawla S, et al “Evaluating the safety and efficacy of denosumab in patients with giant cell tumor of bone (GCTB): Second interim analysis from a phase II study” CIBD 2011; Abstract P53.