Therapies

Denosumab

Xgeva

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SUMMARY

Company: Amgen
Approval Status: FDA Approved June 2013
Specific Treatments: giant cell tumor of bone
Drug: Denosumab

 

GENERAL INFORMATION

Xgeva (denosumab) is a human IgG2 monoclonal antibody that binds to human RANKL. Increased osteoclast activity, stimulated by RANKL, is a mediator of bone pathology in solid tumors with osseous metastases.

Xgeva is specifically indicated for the treatment of adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity.

The recommended dose for giant cell tumor of the bone is 120 mg administered every 4 weeks with additional 120 mg doses on Days 8 and 15 of the first month of therapy. Administer subcutaneously in the upper arm, upper thigh, or abdomen.

 

CLINICAL RESULTS

FDA Approval

The FDA approval of Xgeva for giant cell tumor of bone was based on two open-label trials (Trial 4 and 5). Subjects received 120 mg Xgeva subcutaneously every 4 weeks with additional doses on Days 8 and 15 of the first cycle of therapy. Trial 4 was a single arm, pharmacodynamic, and proof of concept trial conducted in 37 adult patients with unresectable or recurrent giant cell tumor of bone.Trial 5 was a parallel-cohort, proof of concept, and safety trial conducted in 282 adult or skeletally mature adolescent patients with histologically confirmed giant cell tumor of bone and evidence of measurable active disease. Trial 5 enrolled 10 patients who were 13 to 17 years of age. Patients enrolled into one of three cohorts: Cohort 1 enrolled 170 patients with surgically unsalvageable disease; Cohort 2 enrolled 101 patients with surgically salvageable disease where the investigator determined that the planned surgery was likely to result in severe morbidity; Cohort 3 enrolled 11 patients who previously participated in Trial 4. An independent review committee evaluated objective response in 187 patients enrolled and treated in Trials 4 and 5 for whom baseline and at least one post-baseline radiographic assessment were available. The primary endpoint was objective response rate. The overall objective response rate (RECIST 1.1) was 25% and all responses were partial responses. The estimated median time to response was 3 months. In the 47 patients with an objective response, the median duration of follow-up was 20 months and 51% had a duration of response lasting at least 8 months. Three patients experienced disease progression following an objective response.

 

SIDE EFFECTS

Adverse events associated with the use of Xgeva for giant cell tumor of bone may include, but are not limited to, the following:

  • arthralgia
  • headache
  • nausea
  • back pain
  • fatigue
  • pain in extremity

 

MECHANISM OF ACTION

Xgeva (denosumab) binds to RANKL, a transmembrane or soluble protein essential for the formation, function, and survival of osteoclasts, the cells responsible for bone resorption. Increased osteoclast activity, stimulated by RANKL, is a mediator of bone pathology in solid tumors with osseous metastases. Similarly, giant cell tumor of bone consist of stromal cells expressing RANKL and osteoclast-like giant cells expressing RANK receptor, and signaling through the RANK receptor contributes to osteolysis and tumor growth. Xgeva prevents RANKL from activating its receptor, RANK, on the surface of osteoclasts, their precursors, and osteoclast-like giant cells.

Source: centerwatch