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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, thereby modulating calcium release from bone. Increased osteoclast activity, stimulated by RANKL, is a mediator of bone pathology in solid tumors with osseous metastases. Similarly, giant cell tumors 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.
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 once every 4 weeks, up to 2.8-fold accumulation in serum denosumab concentrations was observed and steady state was achieved by 6 months. A mean (± standard deviation) serum steady-state trough concentration of 20.5 (± 13.5) mcg/mL was achieved by 6 months.
With the administration of subcutaneous doses of 120 mg once every 4 weeks with additional 120 mg doses on Days 8 and 15 of the first month of therapy, mean (± standard deviation) serum trough concentrations on Day 8, 15, and one month after the first dose were 19.0 (± 24.1), 31.6 (± 27.3), 36.4 (± 20.6) mcg/mL, respectively. Steady-state was achieved in 3 months after initiation of treatment with a mean serum trough concentration of 23.4 (± 12.1) mcg/mL. The mean elimination half-life was 28 days.
Body Weight: 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.
Age, Gender and Race: The pharmacokinetics of denosumab was not affected by age, gender, and race.
Pediatrics: The pharmacokinetics of denosumab in pediatric patients has 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 clinical trials of 87 patients with varying degrees of renal dysfunction, including patients 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].
Bone Metastasis From Solid Tumors
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 patientswith 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
|Trial 1 Metastatic Breast Cancer||Trial 2 Metastatic Solid Tumors or Multiple Myeloma||Trial 3 Metastatic CRPCa|
|Xgeva||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-value||< 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)|
|Superiority p-value e||0.001||0.145||0.009|
|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.
Giant Cell Tumor Of 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 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 magnetic resonance imaging (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 [see Use in Specific Populations]. 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 intravenous 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.
In this trial, refractory hypercalcemia of malignancy was defined as an albumin-corrected calcium of > 12.5 mg/dL (3.1 mmol/L) despite treatment with intravenous bisphosphonate therapy in 7-30 days prior to initiation of Xgeva 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. Efficacy data are summarized in Figure 1 and Table 3. Concurrent chemotherapy did not appear to affect response to Xgeva.
Figure 1: Corrected Serum Calcium by Visit in
Responders (Median and Interquartile Range)
Table 3: Efficacy in Patients with Hypercalcemia of
Malignancy Refractory to Bisphosphonate Therapy
|N = 33||Proportion (%)
|All Responders (CSC ≤ 11.5 mg/dL) by Day 10||21||63.6
|All Responders by Day 57||23||69.7
|Complete Responders (CSC ≤ 10.8 mg/dL) by Day 10||12||36.4
|All Complete Responders by Day 57||21||63.6
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 ≤ 10.8mg/dL) was 23 days (95% CI: 9, 36), and the median duration of complete response was 34 days (95% CI: 1, 134).
Last reviewed on RxList: 3/9/2016
This monograph has been modified to include the generic and brand name in many instances.
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