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Mechanism of Action
Xgeva binds to RANKL, a transmembrane or 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.
In patients with breast cancer and bone metastases, the median reduction in uNTx/Cr was 82% within 1 week following initiation of Xgeva 120 mg administered subcutaneously. In Trials 1, 2, and 3, the median reduction in uNTx/Cr from baseline to month 3 was approximately 80% in 2075 Xgeva-treated patients.
Following subcutaneous administration, bioavailability was 62%. Denosumab displayed nonlinear pharmacokinetics at doses below 60 mg, but approximately dose-proportional increases in exposure at higher doses. With multiple subcutaneous doses of 120 mg every 4 weeks in patients with cancer metastatic to the bone, up to 2.8-fold accumulation in serum denosumab concentrations was observed and steady state was achieved by 6 months. At steady state, the mean ± SD serum trough concentration was 20.5 ± 13.5 mcg/mL at the recommended Xgeva dose, and the mean elimination half-life was 28 days.
A population pharmacokinetic analysis was performed to evaluate the effects of demographic characteristics. Denosumab clearance and volume of distribution were proportional to body weight. The steady-state exposure following repeat subcutaneous administration of 120 mg every 4 weeks to 45 kg and 120 kg subjects were, respectively, 48% higher and 46% lower than exposure of the typical 66 kg subject.
The pharmacokinetics of denosumab were not affected by age, gender, and race. The pharmacokinetics of denosumab in pediatric patients have not been assessed.
Hepatic Impairment: No clinical trials have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of denosumab.
Renal Impairment: In a trial of 55 subjects with varying degrees of renal function, including subjects on dialysis, the degree of renal impairment had no effect on the pharmacokinetics and pharmacodynamics of denosumab [see Use In Specific Populations].
Animal Toxicology and/or Pharmacology
Denosumab is an inhibitor of osteoclastic bone resorption via inhibition of RANKL.
Because the biological activity of denosumab in animals is specific to nonhuman primates, evaluation of genetically engineered (knockout) mice or use of other biological inhibitors of the RANK/RANKL pathway, OPG-Fc and RANK-Fc, provided additional safety information on the inhibition of the RANK/RANKL pathway in rodent models. A study in 2-week-old rats given the RANKL inhibitor OPG-Fc showed reduced bone growth, altered growth plates, and impaired tooth eruption. These changes were partially reversible in this model when dosing with the RANKL inhibitors was discontinued. Neonatal RANK/RANKL knockout mice also exhibited reduced bone growth and lack of tooth eruption. RANK/RANKL knockout mice also exhibited absence of lymph node formation, as well as an absence of lactation due to inhibition of mammary gland maturation (lobulo-alveolar gland development during pregnancy) [see Use In Specific Populations].
The safety and efficacy of Xgeva for the prevention of skeletal-related events 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 4 weeks or 4 mg zoledronic acid intravenously (IV) every 4 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 skeletal-related event (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 2046 patients with advanced breast cancer and bone metastasis. Randomization was stratified by a history of prior SRE (yes or no), receipt of chemotherapy within 6 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 6 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 1776 adults with solid tumors other than breast and castrate-resistant prostate cancer 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 7 for both denosumab and zoledronic acid.
Trial 3 enrolled 1901 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 (yes or no). Twenty-six percent of patients had a previous SRE, 15% of patients had PSA less than 10 ng/mL, and 14% received chemotherapy within 6 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 castrate-resistant prostate cancer (CRPC) with osseous metastases (Table 2). 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. Mortality was higher with Xgeva in a subgroup analysis of patients with multiple myeloma (hazard ratio [95% CI] of 2.26 [1.13, 4.50]; n = 180).
Table 2: Efficacy Results
for Xgeva Compared to Zoledronic Acid
Metastatic Breast Cancer
Metastatic Solid Tumors or Multiple Myeloma
|Zoledronic Acid||Xgeva||Zoledronic Acid||Xgeva||Zoledronic Acid|
|First On-study SRE|
|Number of Patients who had SREs (%)||315 (30.7)||372 (36.5)||278 (31.4)||323 (36.3)||341 (35.9)||386 (40.6)|
|Components of First SRE|
|Radiation to Bone||82 (8.0)||119 (11.7)||119 (13.4)||144 (16.2)||177 (18.6)||203 (21.3)|
|Pathological Fracture||212 (20.7)||238 (23.3)||122 (13.8)||139 (15.6)||137 (14.4)||143 (15.0)|
|Surgery to Bone||12 (1.2)||8 (0.8)||13 (1.5)||19 (2.1)||1 (0.1)||4 (0.4)|
|Spinal Cord Compression||9 (0.9)||7 (0.7)||24 (2.7)||21 (2.4)||26 (2.7)||36 (3.8)|
|Median Time to SRE (months)||NRb||26.4||20.5||16.3||20.7||17.1|
|Hazard Ratio (95% CI)||0.82 (0.71, 0.95)||0.84 (0.71, 0.98)||0.82 (0.71, 0.95)|
|Noninferiority p-valuec||< 0.001||< 0.001||< 0.001|
|First and Subsequent SREd|
|Rate Ratio (95% CI)||0.77 (0.66, 0.89)||0.90 (0.77, 1.04)||0.82 (0.71, 0.94)|
|aCRPC = castrate-resistant prostate cancer.
bNR = not reached.
cSuperiority testing performed only after denosumab demonstrated to be noninferior to zoledronic acid within trial.
dAll skeletal events postrandomization; new events defined by occurrence ≥ 21 days after preceding event.
eAdjusted p-values are presented.
Last reviewed on RxList: 3/4/2013
This monograph has been modified to include the generic and brand name in many instances.
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