Description
Xgeva is a monoclonal antibody that works to inhibit RANKL (receptor activator of nuclear factor kappa-B ligand) or nuclear factor kB ligand. It is indicated for the prevention of SREs in patients with bone metastases from solid tumors and in patients with multiple myeloma. Xgeva is also indicated for the treatment of giant cell tumor of the bone that is unresectable or in an a rea where surgical resection is likely to result in severe morbidity. In late 2014, Xgeva also received approval for use in hypercalcemia of malignancy refractory to bisphosphonate therapy. In general, RANKL binds to the RANK receptor to increase differentiation and maturation of an osteoclastic precursor into a mature osteoclast. Osteoclasts work to increase bone resorption (in other words, increase the destruction of bone cells in order to release mineral contents within the bone cells). Under normal physiological situations, osteoclastic activity is important in bone development. When the activity is out of control, bone resorption can occur and make the bone more prone to fracture. Xgeva prevents RANKL from activating its receptor, RANK, on the surface of osteoclasts, their precursors, and osteoclast-like giant cells.

Other medications that have been approved for similar indications as Xgeva include Zometa and Aredia. Mechanisms are unclear and differ for each drug. Xgeva is administered subcutaneously every four weeks in a 120 mg dose for the prevention of SREs secondary to bone metastases from solid tumors or multiple myeloma. In patients with giant cell tumor of the bone or hypercalcemia of malignancy refractory to bisphosphonate therapy, Xgeva is dosed at 120 mg every 4 weeks with additional 120 mg doses on days 8 and 15 of the first month of therapy.

SREs are defined as pathologic fractures, surgical/radiotherapy interventions to bone lesions, spinal cord compression and hypercalcemia of malignancy. SREs result in negative quality of life and a worsening of prognosis. Biphosphonates are a standard of care for patients with bone metastasis.

Bone Metastases
Pathophysiology
Sites of bone metastasis are predominantly the axial skeleton, particularly the spine, pelvis, and ribs, where red marrow is most abundant. Bone metastases are classified as either osteolytic (destructive of normal bone) or osteoblastic (involving deposition of new bone) based upon the predominant radiologic appearance. In both types of lesions there is dysregulation of the normal bone remodeling process. Both breast cancer and prostate cancer bone metastases tend to be mixed osteoblastic and osteolytic, although osteolytic lesions generally predominate in breast cancer and osteoblastic lesions generally predominate in prostate cancer.

The bone destruction observed in osteolytic metastases is primarily mediated by osteoclasts and is not a direct effect of tumor cells. In breast cancer, a reciprocal interaction between breast cancer cells and the bone microenvironment results in a "vicious cycle" that increases both bone destruction and tumor burden. Tumor cells produce factors that directly or indirectly induce osteoclast formation. The resulting bone resorption caused by osteoclasts releases growth factors from the bone matrix that stimulate both tumor growth and further bone destruction.

The pathogenesis of osteoblastic metastasis is less well understood than that of osteolytic lesions. Prostate specific antigen (PSA), released from prostate cancer cells, may lead to blockade of tumor-induced bone resorption and to release of osteoblastic growth factors in the bone microenvironment.

Clinical Presentation
Bone metastases can cause a wide range of symptoms that can impair the quality of life or shorten survival. Direct complications of bone involvement include severe pain, pathologic fractures, and epidural spinal cord compression. In addition to these local effects, osteolytic metastases can result in life-threatening hypercalcemia.

Metastatic bone pain is typically described as aching, with insidious onset and gradual increase in severity over weeks to months. However, there are exceptions, such as the sudden onset of back pain that accompanies the collapse of a cancer-containing vertebral body. Nerve root entrapment, a common complication associated with vertebral metastases, may cause a burning and/or radiating type of pain.

Diagnosis
Pain by itself is not a reliable indicator of the presence of bone metastases. Confusion with benign pathology is particularly a problem for elderly patients, in whom degenerative disease and osteoporosis are common. The differential diagnosis of new or increasing bone pain in a patient with malignancy includes:

• Worsening pain from nonmalignant conditions, such as arthritis, disc injury, osteoporosis, degenerative disease and Paget's disease.

• Musculoskeletal discomfort related to physical exertion.

• Treatment-related complications, such as nerve root compression from vertebral body collapse.

Structural information on skeletal damage from metastatic bone disease is best obtained by skeletal radiography supplemented by computerized tomography or magnetic resonance imaging (MRI). Isotope bone scanning is a sensitive but non-specific test to detect the presence of skeletal pathology. Preferential uptake of tracer occurs at sites of active bone formation and is influenced by osteoblastic activity and skeletal vascularity. The bone scan, therefore, reflects not only neoplastic but also traumatic and inflammatory processes. A false-negative scan will occur when there is pure lytic disease

Serum and urinary levels of several biochemical markers of bone metabolism (e.g., C-telopeptide [CTx] and N-telopeptide [NTx], the C-terminal and N-terminal peptides, respectively, of mature type I collagen) are being investigated for their diagnostic and prognostic utility in patients with metastatic bone disease. Urinary NTx levels may have particular clinical relevance.

Giant Cell Tumor of the Bone
Giant cell tumor of the bone is a very rare disease and is typically located towards the end of a bone. The disease is characterized by the presence of multinucleated giant cells and imaging would provide classic features of malignant destruction (lytic destruction, cortical destruction, soft-tissue extension, and pathologic fracture).

Hypercalcemia of Malignancy
Hypercalcemia is not uncommon in patients with malignancy. There are typically three mechanisms by which the hypercalcemia can occur. These include osteolytic metastases, tumor secretion of parathyroid hormone related protein, or tumor production of 1.25-dihydroxyvitamin D. There are two IV bisphosphonates approved for the treatment of hypercalcemia of malignancy (zoledronic acid and pamidronate).

Regulatory Status
FDA-approved indications 

Xgeva is a RANK ligand (RANKL) inhibitor indicated for:

• Prevention of skeletal-related events in patients with bone metastases from solid tumors.

• Treatment of giant cell tumor on bone (in adults and skeletally mature adolescents) that is unresectable or where surgical resection is likely to result in severe morbidity.

• Treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy.

• Prevention of skeletal-related events in patients with multiple myeloma.

Xgeva is contraindicated in patients with hypocalcemia. Pre-existing hypocalcemia must be corrected prior to initiating therapy with Xgeva.

Xgeva may increase risk for osteonecrosis of the jaw, hypocalcemia, and atypical femoral fracture.

Policy
Xgeva is considered MEDICALLY NECESSARY for treatment of skeletal prevention in multiple myeloma and bone metastasis from solid tumors (BMST) when one of the following criteria are met:

1. Diagnosis of multiple myeloma AND Trial and failure, intolerance, or contraindication to one bisphosphonate (e.g., zoledronic acid), OR patient is currently receiving therapy

2. Diagnosis of solid tumors (e.g., breast cancer, kidney cancer, lung cancer, prostate cancer, thyroid cancer), AND documented evidence of one or more metastatic bone lesions 

Xgeva is considered MEDICALLY NECESSARY for treatment of giant cell tumor of bone when one for the following criteria has been met:

1. Tumor is unresectable.

2. Surgical resection is likely to result in severe morbidity.

Xgeva is considered MEDICALLY NECESSARY for treatment of hypercalcemia of malignancy when one of the following criteria are met:

• Diagnosis of multiple myeloma; AND trial and failure, intolerance, or contraindication to one bisphosphonate (e.g., zoledronic acid); OR patient is currently receiving therapy

Continued treatment with Xgeva is considered MEDICALLY NECESSARY when the following criteria are met:

• Documentation of positive clinical response and patient does not show evidence of progressive disease while on Xgeva therapy. 

BlueCross BlueShield of South Carolina recognizes uses and indications of injectable oncology medications (including chemotherapy/systemic therapy, therapeutic radiopharmaceuticals and selected supportive therapies) to be MEDICALLY NECESSARY if they are listed in the NCCN Drugs and Biologics Compendium with Categories of Evidence + Consensus of 1, 2A and 2B. Treatments listed with a Category of Evidence and Consensus of 3 are considered investigational/unproven therefore NOT MEDICALLY NECESSARY.  

Rationale
Skeletal Related Events Secondary to Bone Metastases from Solid Tumors
The safety and efficacy of Xgeva for the prevention of SREs in patients with bone metastases from solid tumors was demonstrated in three international, randomized (1:1), double-blind, active, controlled, noninferiority trials comparing Xgeva with zoledronic acid. In all three trials, patients were randomized to receive 120 mg Xgeva subcutaneously every four weeks or 4 mg zoledronic acid IV every four weeks (dose adjusted for reduced renal function). Patients with creatinine clearance less than 30 mL/min were excluded. In each trial, the main outcome measure was demonstration of noninferiority of time to first SRE as compared to zoledronic acid. Supportive outcome measures were superiority of time to first SRE and superiority of time to first and subsequent SRE; testing for these outcome measures occurred if the main outcome measure was statistically significant. An SRE was defined as any of the following: pathologic fracture, radiation therapy to bone, surgery to bone, or spinal cord compression.

Trial 1 enrolled 2,046 patients with advanced breast cancer and bone metastasis. Randomization was stratified by a history of prior SRE (yes or no), receipt of chemotherapy within six weeks prior to randomization (yes or no), prior oral bisphosphonate use (yes or no), and region (Japan or other countries). Forty percent of patients had a previous SRE, 40% received chemotherapy within six weeks prior to randomization, 5% received prior oral bisphosphonates, and 7% were enrolled from Japan. Median age was 57 years, 80% of patients were white, and 99% of patients were women. The median number of doses administered was 18 for denosumab and 17 for zoledronic acid.

Trial 2 enrolled 1,776 adults with solid tumors other than breast and castrate-resistant prostate cancer (CRPC) with bone metastasis and multiple myeloma. Randomization was stratified by previous SRE (yes or no), systemic anticancer therapy at time of randomization (yes or no), and tumor type (non-small cell lung cancer, myeloma, or other). Eighty-seven percent were receiving systemic anticancer therapy at the time of randomization, 52% had a previous SRE, 64% of patients were men, 87% were White, and the median age was 60 years. A total of 40% of patients had non -small cell lung cancer, 10% had multiple myeloma, 9% had renal cell carcinoma, and 6% had small cell lung cancer. Other tumor types each comprised less than 5% of the enrolled population. The median number of doses administered was seven for both denosumab and zoledronic acid.

Trial 3 enrolled 1901 men with CRPC 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 (yes or no). Twenty-six percent of patients had a previous SRE, 15% of patients had PSA less than 10ng/mL, and 14% received chemotherapy within six weeks prior to randomization. Median age was 71 years and 86% of patients were white. The median number of doses administered was 13 for denosumab and 11 for zoledronic acid.

Xgeva delayed the time to first SRE following randomization as compared to zoledronic acid in patients with breast or CRPC 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 a cid in delaying the time to first SRE following randomization. Overall survival and progression -free survival were similar between arms in all three trials. Mortality was higher with Xgeva in a subgroup analysis of patients with multiple myeloma (hazard ratio [95% confidence interval or CI] of 2.26 [1.13, 4.50]; n = 180).

Giant Cell Tumor of the Bone
The safety and efficacy of Xgeva for the treatment of giant cell tumor of bone in adults or skeletally mature adolescents were demonstrated in two open-label trials (Trial 4 and Trial 5) that enrolled patients with histologically confirmed measurable giant cell tumor of bone that was either recurrent, unresectable, or for which planned surgery was likely to result in severe morbidity. Patients 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. Patients were required to have histologically confirmed giant cell tumor of bone and radiologic evidence of measurable disease from a computed tomography (CT) or MRI obtained within 28 days prior to study enrollment. Patients enrolled in Trial 4 underwent CT or MRI assessment of giant cell tumor of bone at baseline and quarterly during Xgeva treatment.

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 – 17 years of age. Patients enrolled into one of three cohorts: Cohort 1 enrolled 170 patients with surgically unsalvageable disease (e.g., sacral or spinal sites of disease or pulmonary metastases); Cohort 2 enrolled 101 patients with surgically salvageable disease where the investigator determined that the planned surgery was likely to result in severe morbidity (e.g., joint resection, limb amputation or hemipelvectomy); Cohort 3 enrolled 11 patients who previously participated in Trial 4. Patients underwent imaging assessment of disease status at intervals determined by their treating physician.

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 (27 of 37 patients enrolled in Trial 4 and 160 of 270 patients enrolled in Cohorts 1 and 2 of Trial 5). The primary efficacy outcome measure was objective response rate using modified Response Evaluation Criteria in Solid Tumors (RECIST 1.1).

The overall objective response rate (RECIST 1.1) was 25% (95% CI: 19, 32). 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 (range: 2 to 44 months), and 51% (24/47) had a duration of response lasting at least 8 months. Three patients experienced disease progression following an objective response.

Hypercalcemia of Malignancy
The safety and efficacy of Xgeva was demonstrated in an open-label, single-arm trial (Trial 6) that enrolled 33 patients with hypercalcemia of malignancy (with or without bone metastases) refractory to treatment with IV bisphosphonate therapy. Patients received Xgeva subcutaneously every 4 weeks with additional 120 mg doses on Days 8 and 15 of the first month of therapy. The primary outcome measure was the proportion of patients achieving a response, defined as corrected serum calcium (CSC) ≤ 11.5 mg/dL (2.9 mmol/L), within 10 days after Xgeva administration. The proportion of responders achieving a response by day 10 was 63.6%. The proportion of patients that were responders by day 57 was 69.7%. Median time to response (CSC < 11.5 mg/dL) was 9 days (95% CI: 8, 19), and the median duration of response was 104 days (95% CI: 7, not estimable). Median time to complete response (CSC < 10.8 mg/dL) was 23 days (95% CI: 9, 36), and the median duration of complete response was 34 days (95% CI: 1, 134). Concurrent chemotherapy did not appear to affect response to Xgeva.

Multiple Myeloma
The efficacy of Xgeva for the prevention of SREs was evaluated in an international, randomized, double-blind, active-controlled, noninferiority trial comparing Xgeva with zoledronic acid in 1,718 newly diagnosed multiple myeloma patients with bone lesions. Patients were randomized 1:1 to receive 120 mg Xgeva subcutaneously every 4 weeks or 4 mg zoledronic acid intravenously every 4 weeks. The main efficacy outcome measure was noninferiority of time to first SRE, time to first and subsequent SRE, and overall survival. An SRE was defined as any of the following: pathologic fracture, radiation therapy to bone, surgery to bone, or spinal cord compression.

Xgeva was found to be noninferior to zoledronic acid in delaying the time to first SRE following randomization (HR = 0.98, 95% CI, 0.85 – 1.14). The results for overall survival were comparable between Xgeva and zoledronic acid treatment groups with a hazard ratio of 0.9 (95% CI: 0.7, 1.16).

References

1. U.S. Food and Drug Administration. Labeling of the drug denosumab (Xgeva ). June 2014. http://www.fda.gov
2. Xgeva. [package insert]. Amgen: Thousand Oaks, California. 2018.
3. Beers M, Porter R, Jones T, Kaplan J, Berkwits M. The Merck Manual of Diagnosis and Therapy. Whitehouse Station, NJ: Merck Research Laboratories; 2006.

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