Xgeva (denosumab)

The following drug information is obtained from various newswires, published medical journal articles, and medical conference presentations.

Company:

Approval Status:

Approved November 2010

Specific Treatments:

prevention of skeletal-related events in patients with bone metastases from solid tumors

Therapeutic Areas

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General Information

Xgeva (denosumab) is a human IgG2 monoclonal antibody that binds to human RANKL, a transmembrane (soluble protein) essential for the formation, function, and survival of osteoclasts, the cells responsible for bone resorption. Xgeva prevents RANKL from activating its receptor, RANK, on the surface of osteoclasts and their precursors. Increased osteoclast activity, stimulated by RANKL, is a mediator of bone pathology in solid tumors with osseous metastases.

Xgeva is specifically indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors.

Xgeva is supplied as a solution designed to subcutaneous administration. The recommended dose of Xgeva is 120 mg administered as a subcutaneous injection every 4 weeks in the upper arm, upper thigh, or abdomen.

Clinical Results

FDA Approval
The FDA approval of Xgeva was based on three international, randomized, double-blind, active-controlled, non-inferiority trials comparing Xgeva with zoledronic acid. The subjects were randomized to receive 120 mg Xgeva subcutaneously every 4 weeks or 4 mg zoledronic acid intravenously (IV) every 4 weeks. The main outcome measure was demonstration of non-inferiority of time to first skeletal-related event (SRE) as compared to zoledronic acid. An SRE was defined as any of the following: pathologic fracture, radiation therapy to bone, surgery to bone, or spinal cord compression.
Trial One
This trial enrolled 2,046 patients with advanced breast cancer and bone metastasis. Randomization was stratified by a history of prior SRE, receipt of chemotherapy within 6 weeks prior to randomization, prior oral bisphosphonate use and region. The median number of doses administered was 18 for denosumab and 17 for zoledronic acid.
Trial Two
This trial enrolled 1,776 adults with solid tumors other than breast and castrate-resistant prostate cancer with bone metastasis and multiple myeloma. Randomization was stratified by previous SRE, systemic anticancer therapy at time of randomization and tumor type (non-small cell lung cancer, myeloma, or other). The median number of doses administered was 7 for both denosumab and zoledronic acid.
Trial Three
This trial enrolled 1,901 men with castrate-resistant prostate cancer and bone metastasis. Randomization was stratified by previous SRE, PSA level (less than 10 ng/mL or 10 ng/mL or greater) and receipt of chemotherapy within 6 weeks prior to randomization. The median number of doses administered was 13 for denosumab and 11 for zoledronic acid.
Pooled Data
Xgeva delayed the time to first SRE following randomization as compared to zoledronic acid in patients with breast or castrate-resistant prostate cancer with osseous metastases. In patients with bone metastasis due to other solid tumors or lytic lesions due to multiple myeloma, Xgeva was noninferior to zoledronic acid in delaying the time to first SRE following randomization. Overall survival and progression-free survival were similar between arms in all three trials.

Side Effects

Adverse events associated with the use of Xgeva may include, but are not limited to, the following:

  • Fatigue/asthenia
  • Hypophosphatemia
  • Nausea

Mechanism of Action

Xgeva (denosumab) is a human IgG2 monoclonal antibody that binds to human RANKL, a transmembrane (soluble protein) essential for the formation, function, and survival of osteoclasts, the cells responsible for bone resorption. Xgeva prevents RANKL from activating its receptor, RANK, on the surface of osteoclasts and their precursors. Increased osteoclast activity, stimulated by RANKL, is a mediator of bone pathology in solid tumors with osseous metastases.

Literature References

Stopeck AT, Lipton A, Body JJ, Steger GG, Tonkin K, de Boer RH, Lichinitser M, Fujiwara Y, Yardley DA, Viniegra M, Fan M, Jiang Q, Dansey R, Jun S, Braun A Denosumab Compared With Zoledronic Acid for the Treatment of Bone Metastases in Patients With Advanced Breast Cancer: A Randomized, Double-Blind Study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2010 Nov 8

Fizazi K, Bosserman L, Gao G, Skacel T, Markus R Denosumab treatment of prostate cancer with bone metastases and increased urine N-telopeptide levels after therapy with intravenous bisphosphonates: results of a randomized phase II trial. The Journal of urology 2009 Aug;182(2):509-15

Fizazi K, Lipton A, Mariette X, Body JJ, Rahim Y, Gralow JR, Gao G, Wu L, Sohn W, Jun S Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2009 Apr 1;27(10):1564-71

Additional Information

For additional information regarding Xgeva or skeletal-related events in patients with bone metastases from solid tumors, please visit the Xgeva web page.