General Information

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

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.

Xgeva is specifically indicated for the treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy.

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.

Side Effects

Adverse events associated with the use of Xgeva for prevention of skeletal-related events in patients with bone metastases from solid tumors may include, but are not limited to, the following:

• Fatigue/asthenia
• Hypophosphatemia
• Nausea

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

• Arthralgia
• Headache
• Nausea
• Back pain
• Fatigue
• Pain in extremity

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

• Nausea
• Dyspnea
• Decreased appetite
• Headache
• Peripheral edema
• Vomiting
• Anemia
• Constipation
• Diarrhea

Dosing/Administration

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 four weeks in the upper arm, upper thigh or abdomen.

The recommended dose for giant cell tumor of the bone is 120 mg administered every four 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.

For hypercalcemia of malignancy refractory to bisphosphonate therapy, the recommended dose of Xgeva is 120 mg administered every four 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 Trial Results

Prevention of skeletal-related events in patients with bone metastases from solid tumors: 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 four weeks or 4 mg zoledronic acid intravenously (IV) every four 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 six 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 seven 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 six 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.

The FDA approval of Xgeva for giant cell tumor of bone was based on two open-label trials (Trials 4 and 5). Subjects received 120 mg Xgeva subcutaneously every four 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 end point was objective response rate. The overall objective response rate (RECIST 1.1) was 25 percent, and all responses were partial responses. The estimated median time to response was three months. In the 47 patients with an objective response, the median duration of follow-up was 20 months, and 51 percent had a duration of response lasting at least eight months. Three patients experienced disease progression following an objective response.

The FDA approval of Xgeva for hypercalcemia was based on results from an open-label, single-arm study involving patients with advanced cancer and persistent hypercalcemia after recent bisphosphonate treatment. The primary end point was the proportion of patients with a response, defined as albumin-corrected serum calcium (CSC) <11.5 mg/dL (2.9 mmol/L; Common Terminology for Adverse Events [CTCAE] grade <1) within 10 days after the first dose of Xgeva. Secondary end points included the proportion of patients who experienced a complete response (defined as CSC <10.8 mg/dL [2.7 mmol/L]) by Day 10, time to response and response duration (defined as the number of days from the first occurrence of CSC <11.5 mg/dL). The study achieved its primary end point with a response rate at Day 10 in 63.6 percent of the 33 patients evaluated (i.e., overall response rate = 63.6 percent). The estimated median time to response (CSC <11.5 mg/dL) was nine days, and the median duration of response was 104 days.