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Cancer Therapy: Clinical |
B Ligand Inhibitor, Denosumab, in Patients with Multiple Myeloma or Bone Metastases from Breast Cancer
Authors' Affiliations: 1 Department of Medicine, Institut Jules Bordet, Brussels, Belgium; 2 Service Des Maladies du Sang, CHU de Lille, Lille, France; 3 Cancer Research Centre, Weston Park Hospital, Sheffield, United Kingdom; 4 Division of Hematology/Oncology, Penn State Hershey Medical Center, Hershey, Pennsylvania; and 5 Amgen, Inc., Thousand Oaks, California
Requests for reprints: Jean-Jacques Body, Department of Medicine, Institut Jules Bordet, Rue Héger Bordet 1, B-1000 Brussels, Belgium. Phone: 32-2-541-3303; Fax: 32-2-541-3310; E-mail: jj.body{at}bordet.be.
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Abstract |
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B ligand (RANKL) is essential for the differentiation, function, and survival of osteoclasts, which play a key role in establishment and propagation of skeletal disease in patients with multiple myeloma or bone metastases as well as many other skeletal diseases. Denosumab (AMG 162), a fully human monoclonal antibody to RANKL, was developed to treat patients with skeletal diseases. Experimental Design: This was a randomized, double-blind, double-dummy, active-controlled, multicenter study to determine the safety and efficacy of denosumab in patients with breast cancer (n = 29) or multiple myeloma (n = 25) with radiologically confirmed bone lesions. Patients received a single dose of either denosumab (0.1, 0.3, 1.0, or 3.0 mg/kg s.c.) or pamidronate (90 mg i.v.). Bone antiresorptive effect was assessed by changes in urinary and serum N-telopeptide levels. Pharmacokinetics of denosumab also were assessed.
Results: Following a single s.c. dose of denosumab, levels of urinary and serum N-telopeptide decreased within 1 day, and this decrease lasted through 84 days at the higher denosumab doses. Pamidronate also decreased bone turnover, but the effect diminished progressively through follow-up. Denosumab injections were well tolerated. Mean half-lives of denosumab were 33.3 and 46.3 days for the two highest dosages.
Conclusions: A single s.c. dose of denosumab given to patients with multiple myeloma or bone metastases from breast cancer was well tolerated and reduced bone resorption for at least 84 days. The decrease in bone turnover markers was similar in magnitude but more sustained than with i.v. pamidronate.
Despite the availability of bisphosphonates, such as zoledronic acid and pamidronate, for the treatment of skeletal complications that result from multiple myeloma or bone metastases, an unmet medical need exists for a more convenient, effective, and safe therapy. Parenteral bisphosphonates must be administered by i.v. infusion. They are not effective in all patients, and renal toxicity (6, 7) and osteonecrosis (8) may limit the dose and use of these agents in certain patients.
A triad of molecules has been shown to regulate osteoclast maturation, differentiation, and survival: receptor activator of nuclear factor-B (RANK), RANK ligand (RANKL), and osteoprotegerin. RANKL, a member of the tumor necrosis factor family, binds to RANK on preosteoclasts and mature osteoclasts, and mediates the differentiation, function, and survival of osteoclasts (9–11). Osteoprotegerin, a natural soluble decoy receptor of RANKL, modulates the effect of RANKL (12, 13) and is able to prevent excessive bone resorption in the normal state. RANKL is a key mediator in the pathogenesis of a broad range of skeletal diseases. For example, tumor cells may express RANKL (14, 15) and tumor factors, such as parathyroid hormone-related protein, may up-regulate RANKL expression in patients with cancer, causing excessive bone resorption (16). In particular, RANKL expression is elevated in patients with multiple myeloma (17, 18) and in some breast cancer cell lines (16).
Denosumab (AMG 162; Amgen, Inc., Thousand Oaks, CA) is a fully human monoclonal antibody to RANKL that has high affinity and specificity for RANKL. It was developed to treat patients with skeletal diseases mediated by osteoclasts, such as bone metastasis, multiple myeloma, and hormone ablation–induced bone loss in patients with cancer. As a human IgG2 molecule, denosumab was shown to have a long circulatory residence time and result in a rapid and sustained decrease of bone resorption in healthy postmenopausal women following a single s.c. dose (7). Because denosumab does not neutralize murine or rodent RANKL, it cannot be studied in typical animal models of bone metastasis. However, osteoprotegerin, which similarly blocks RANKL/RANK interaction, was shown to be effective in animal models of bone metastasis and multiple myeloma (19–22).
This clinical trial was conducted to investigate the safety, pharmacokinetics, and pharmacodynamics of denosumab in patients with multiple myeloma or bone metastases from breast cancer. The effects of denosumab were compared with those of the bisphosphonate pamidronate.
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Materials and Methods |
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Patients. Women with breast cancer and radiological evidence of lytic or mixed bone metastases were enrolled into one disease stratum and patients with multiple myeloma and evidence of lytic bone disease were enrolled into the second disease stratum at four centers in the United States and Europe. Patients were at least 18 years old and were ambulatory. Patients were excluded if they had disorders of the parathyroid or thyroid glands, osteomalacia, rheumatoid arthritis, flare-up of osteoarthritis or gout, Paget's disease, malabsorption syndrome, ascites, a long-bone fracture within 90 days before dosing, serum creatinine >221 µmol/L, serum bilirubin >43 µmol/L, or albumin-adjusted serum calcium 
2.62 mmol/L. Serum albumin–adjusted calcium levels were calculated as observed serum calcium level (mmol/L) – [0.02 x albumin (g/L)] + 0.8.
All patients provided written informed consent before enrollment, and the study was approved by the local Institutional Review Board or Ethics Committee for each site.
Study procedures. On the morning of dosing, patients received double-dummy therapy consisting of s.c. injections plus a 4-hour i.v. infusion–denosumab s.c. plus saline i.v., or placebo s.c. plus pamidronate i.v. Medications affecting bone metabolism, such as bisphosphonates, were not allowed for 60 days before randomization and they were not to be scheduled for 56 days following randomization. However, if the urinary N-telopeptide (NTX) levels had not decreased within 28 days after study drug administration, the investigator could initiate bisphosphonate therapy. Chemotherapy within 21 days before randomization or within 21 days following dosing also was not allowed because it could influence the bone turnover marker response. Patients who received chemotherapy within 21 days before dosing were only allowed into the study if urinary NTX was 30 nmol bone collagen equivalent/mmol creatinine at enrollment. Other treatments that were not permitted included surgery to bone or long-bone fracture within 90 days, local radiation to bone within 28 days, or glucocorticoid treatment within 14 days either before or after dosing.
Patients were followed for 84 days; study visits were scheduled for days 1, 2, 3, and 4, and then weeks 1, 2, 3, 4, 6, 8, 10, and 12. Radiological assessment, medical history, medication history, and bone involvement (using diagrams with guidelines for estimating percentage involvement) were recorded prestudy. The following procedures were done prestudy and periodically during the study to assess outcomes: physical examinations, vital signs, hematology, serum chemistry, and antidenosumab antibodies. To assess the effect of denosumab administration on bone metabolism, urinary and serum NTX (Osteomark, Seattle, WA), serum bone-specific alkaline phosphatase (Tandem-R Ostase, Hybritech, Inc, San Diego, CA), and serum albumin–adjusted calcium were assessed prestudy and periodically following dosing. Urinary NTX levels were assessed on a second morning void and were corrected for creatinine concentration. Bone turnover marker samples were drawn during screening and study day 1 before dosing; the baseline value for bone turnover markers was defined to be the average of these values. Adverse events, laboratory variables, and concomitant medications were assessed at all study visits following dosing.
Pharmacokinetic analyses were based on blood samples drawn at baseline; 1, 2, 4, 8, and 24 hours after dosing; and then at every study visit. Serum levels of denosumab were determined using a solid-phase sandwich enzyme immunoassay technique. Denosumab in serum was captured by RANKL bound to microtiter plates and detected by RANKL conjugated to horseradish peroxidase.
Statistical analysis. Data from the dose-escalation phase and the parallel-dosing phase of the study were combined for descriptive statistical analyses. As prospectively specified per protocol, data were summarized by disease stratum. The data for denosumab within each disease stratum were pooled across the two phases of the study into the appropriate dose cohorts (0.1, 0.3, 1.0, and 3.0 mg/kg). In addition, data from the patients randomized to pamidronate within each of the four cohorts were combined to provide a single pooled pamidronate group of five patients in each disease stratum for comparison with the denosumab dose cohorts. Formal comparative statistical analysis of the data was not done due to the small sample sizes and the exploratory nature of the study.
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Results |
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Transient early reductions in albumin-adjusted serum calcium were seen in most treatment groups, but median values remained within the reference range. Two patients had serum calcium below 2 mmol/L, but neither patient was reported to have symptoms of hypocalcemia. The first patient was in the breast cancer stratum and had a baseline calcium level of 2.25 mmol/L that decreased to 1.98 mmol/L 15 days after a single s.c. dose of denosumab 0.1 mg/kg but returned to normal (2.18 mmol/L) by the next measurement on day 29. The second patient was in the multiple myeloma stratum and received a dose of denosumab 0.3 mg/kg; albumin-adjusted calcium in this patient was 2.18 mmol/L on day 1, which decreased to a nadir of 1.93 mmol/L on days 8 and 15, returned to 2.25 mmol/L on day 29, and remained >2 mmol/L thereafter. The patient was reported to have paresthesia on day 29 when the hypocalcemia had already resolved. An adverse event of hypocalcemia was reported for one patient with breast cancer who received a dose of denosumab 0.3 mg/kg, but her albumin-adjusted serum calcium remained >2 mmol/L at every visit, with a nadir of 2.13 mmol/L on day 8. No symptoms of hypocalcemia were reported.
Safety and tolerability. Denosumab injections were well tolerated; no injection site reactions were reported. In the breast cancer stratum, serious adverse events were reported for three patients who received denosumab 0.1 mg/kg (one had progression of malignancy, a second had a concussion following a car accident, and a third had hip fracture and progression of bone metastases) and two patients who received denosumab 0.3 mg/kg (one had supraventricular tachycardia, liver metastases, pleural effusion, ascites, and pulmonary embolism; and another had progression of bone metastases). In the multiple myeloma stratum, serious adverse events were reported for one patient in the pamidronate group (multiple myeloma progression) and one who received denosumab 0.1 mg/kg (pathologic clavicular fracture and progression of multiple myeloma). Investigators did not consider any of these serious adverse events to be related to study drug.
The most commonly reported adverse event was fatigue in the breast cancer stratum (25% denosumab and 40% pamidronate) and asthenia in the multiple myeloma stratum (20% in each group). No clinically significant changes in other laboratory variables were noted. All patients had postexposure blood samples assayed for antidenosumab antibodies; all tests were negative.
Pharmacokinetics. Denosumab exhibited nonlinear, dose-dependent pharmacokinetics. Following s.c. administration, denosumab showed rapid and prolonged absorption with serum levels that were detectable as early as 1 hour postdose and average maximum serum concentrations occurring between 7 and 21 days postdose. Compared with the lowest dose (0.1 mg/kg), the highest dose (3.0 mg/kg) resulted in 116-fold greater area under the concentration curve (AUC0–t) in patients with breast cancer. The increase in Cmax was closer to linear in patients with multiple myeloma, but the half-life was still increased 5-fold at the highest dose, consistent with a 44-fold greater AUC0–t for the 3.0 mg/kg dose compared with the 0.1 mg/kg dose. At 3.0 mg/kg, patients in both the breast cancer stratum and the multiple myeloma stratum showed sustained denosumab concentrations throughout study with mean half-lives of 46.3 and 33.3 days, respectively. Mean serum concentrations of denosumab were >5,000 ng/mL throughout the observation period after a single s.c. dose of 3.0 mg/kg and >1,000 ng/mL throughout the observation period after a single s.c. dose of 1.0 mg/kg (Fig. 4).
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Discussion |
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Despite the availability of potent bisphosphonates, such as pamidronate, ibandronate, and zoledronic acid, an unmet medical need exists for a more convenient, safe, and effective therapy. Denosumab is administered by s.c. bolus injection, eliminating the need for i.v. infusion. Furthermore, available parenteral bisphosphonates are infused once every 3 to 4 weeks in patients with skeletal metastases or osteolytic lesions (23–28), but the dosing schedule for denosumab may be more flexible, based on the persistent bone turnover suppression that was evident through 84 days of follow-up in this study.
Although no statistical testing was done due to the small number of patients in each group, the duration of bone turnover suppression seemed to be much longer with higher doses of denosumab compared with pamidronate, which is one of the standard therapies for patients with multiple myeloma or bone metastases due to breast cancer (24–28). As observed in other studies, bone resorption seemed to resume 3 to 4 weeks after pamidronate administration (29). The inhibitory effects of denosumab lasted for at least 3 months, with similar pharmacodynamics and pharmacokinetics between the two highest doses of denosumab. This greater efficacy could be partly due to the prolonged circulatory residence time of denosumab, whereas bisphosphonates disappear rapidly from the blood after administration (30). Denosumab concentrations remained elevated after a dose of 3.0 mg/kg in both disease strata of this study, and a study in healthy postmenopausal women (7) showed that denosumab may remain detectable for up to 9 months or longer after a single dose. The half-life of denosumab is also longer than that of osteoprotegerin-Fc, for which the efficacy on bone turnover markers was similar to that of pamidronate (31). The prolonged half-life of denosumab may be due to recycling through the neonatal Fc receptor (32), glycosylation to prevent proteolytic degradation (33), and evasion of breakdown by the immune system because denosumab is a fully human immunoglobulin. The potency and specificity of denosumab to inhibit osteoclast formation, activity, and survival may have contributed to the greater effectiveness documented in this study.
The tolerability of denosumab seems to be another potential advantage. No cases of symptomatic or persistent hypocalcemia were observed. A few serious adverse events occurred during the study, none of which were considered by the investigator to be related to study treatment. There was no evidence of nephrotoxicity in the denosumab cohorts. Renal toxicity (6, 34) is a potential complication of zoledronic acid and pamidronate administration, and osteonecrosis of the jaw, although quite rare, is another potential complication of bisphosphonates (8). The possible nephrotoxicity of certain bisphosphonates limits their dose and use in certain patients.
In a head-to-head trial between a third- and a second- generation bisphosphonate (23), the superiority of zoledronic acid compared with pamidronate could only be shown in breast cancer using a multiple-event analysis. Accordingly, recently updated American Society of Clinical Oncology guidelines on the use of bisphosphonates in patients with breast cancer do not recommend one of these bisphosphonates over the other (35). Moreover, a similar multiple-event analysis did not show that zoledronic acid led to better results than pamidronate in myeloma patients (23). Recently published data with ibandronate suggest a similar efficacy profile because the reduction in event rate was 
40% (36–38). These recent trials suggest that a ceiling effect seems to have been reached with currently available bisphosphonates, at least with the currently recommended therapeutic regimens.
The potential association between pharmacodynamic effects on bone resorption and clinical effects is supported by results of denosumab studies in postmenopausal women. In a placebo-controlled study in healthy postmenopausal women, the extent of bone turnover suppression was similar to that observed in this study and persisted for up to 9 months after a s.c. dose of denosumab 3.0 mg/kg (7). A subsequent study of postmenopausal women with low bone mineral density confirmed that multiple doses of denosumab persistently decreased bone turnover markers and increased bone mineral density (39). Denosumab must now be tested in long-term head-to-head trials with bisphosphonates to determine if increased efficacy on bone resorption variables translates into better clinical efficacy in patients with tumor bone disease. Recent data show a link between the normalization of bone resorption rate, as evaluated by NTX determination, and the beneficial effects of zoledronic acid on the complications of tumor bone disease (40, 41). A strong correlation between the rate of bone resorption and the frequency of skeletal complications in metastatic bone disease has thus been found in breast cancer and other tumors.
Denosumab is a specific, fully human, monoclonal antibody to RANKL that would not resemble osteoprotegerin structurally, so any antibodies to denosumab would not be expected to neutralize endogenous osteoprotegerin. Indeed, no evidence of such effect was seen in this trial, another single-dose study of denosumab (7), or a previous study using AMGN-0007 (a genetically engineered osteoprotegerin-Fc construct) in 39 patients with breast cancer metastatic to bone or multiple myeloma (31).
Limitations of this study include its small size, study medication was administered to each patient only once, and the study population had relatively low bone turnover at baseline. Larger, longer studies are ongoing to investigate the pharmacokinetics, pharmacodynamics, efficacy, and safety of multiple-dose therapy with denosumab in patients with skeletal disorders, including breast cancer, multiple myeloma, and other solid tumors.
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Footnotes |
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Note: Results from this study were presented at the Fourth International Conference on Cancer-Induced Bone Diseases, San Antonio, Texas, in 2003 and at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, in 2004.
Received 9/ 2/05; revised 11/29/05; accepted 12/ 7/05.
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B ligand (RANKL) is a key molecule of osteoclast formation for bone metastasis in a newly developed model of human neuroblastoma. Cancer Res 2001;61:1637–44.B ligand-osteoprotegerin ratio predicts survival in multiple myeloma: proposal for a novel prognostic index. Blood 2003;102:1064–9.This article has been cited by other articles:
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, pamidronate 90 mg i.v.; 
, denosumab 0.1 mg/kg s.c.; 
, denosumab 0.3 mg/kg s.c.; 
, denosumab 1.0 mg/kg s.c.; 
, denosumab 3.0 mg/kg s.c.
