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Denosumab in bone metastasis
of cancer and hypercalemia
Supervisor: 趙大中 大夫
Reporter: 郭政裕 總醫師
Case presentation
• 40 y/o female
• Left breast lump with pain for one year
• Rapid growth with ulceration and bloody
discharge in recent 2 months
• Admission in 2012/12
• invasive ductal
carcinoma of left breast
with multiple metastases
of bone, liver and lymph
node
• albumin-corrected
serum calcium: 16.74
mg/dL
• BUN/Cr 63/3.57
( estimated creatinine
clearance: 15 ml/min )
• How to treat hypercalcemia of malignancy
(HCM) ?
– Vigorous saline hydration
– Loop diuretic after volume expansion
– Bisphosphonates (BPs) ??
• Zoledronic acid
• Pamidronate
• FDA approval of BPs
– Multiple myeloma and bone metastases of solid
tumor
– Hypercalcemia of malignancy
• Renal insufficiency
– Bone-modifying agent for cancer
• CCr < 30 ml/min is not recomment
• CCr 30~60 ml/min  reduce dose of zoledronic acid
– Hypercalcemia of malignancy
• Creatinine ≦ 4.5 mg/dL ?
Zoledronate and acute renal failure
Kidney International, Vol. 64 (2003), pp. 281–289, Markowitz et al
• Bone resorption inhibitor: bisphosphate vs.
denosumab
• Denosumab (FDA approval)
– Osteoporosis
– ↓ skeletal-related events of maliganancy with
bone metastases
– Hypercalcemia (X): ongoing trial
RANKL: receptor activator of
neuclear factor kappa ligand:
a essential signal to
stimulate differentiation,
activity and survival of
osteoclast
Denosumab: a fully
human monoclonal
antibody to RANKL
Animal study
• Immunodeficient mice with human prostate
cancer cells  injection OPG
– OPG markedly reduces osteoclast numbers in
bone lesions ( 12 hours, ↓ up to 95% osteoclast )
– 10~30 days, return to normal
– a progressive increase in bone mineral density
1. Osteoprotegerin inhibits prostate cancer-induced osteoclastogenesis and prevents
prostate tumor growth in the bone, Zhang J, et al, J Clin Invest 2001;107:1235–1244
2. Sustained antiresorptive effects after a single treatment with human recombinant
osteoprotegerin (OPG), Capparelli C, et al, J Bone Miner Res 2003;18:852–858
• OPG treatment in monkeys
– biochemical markers of bone turnover ↓
– ionized calcium and phosphorus ↓, secondary
increase in serum PTH levels
– Increased BMD
• Denosumab treatment in monkeys
– Increased BMD
1. A toxicity profile of osteoprotegerin in the cynomolgus monkey, Smith BB, et al, Int J
Toxicol 2003;22:403–412
2. A fully human RANK-L antibody, increases bone mass and bone strength in
cynomolgus monkeys, Atkinson J, et al, J Bone Miner Res 2005;20:S29
• Skeletal-related events
– Pain
(radiation or surgery treatment)
– Fracture
– Spinal cord compression
– Hypercalcemia
Inclusion criteria:
• Adenocarcinoma of breast
• ≧ 18 y/o
• bone metastasis
• ECOG: 0~2
• creatinine clearance ≧ 30 mL/min
Inclusion criteria
• solid tumor (except breast
and prostate ) or multiple
myeloma
• ≧ 18 y/o
• bone metastasis
• ECOG: 0~2
• creatinine clearance ≧ 30
mL/min
Inclusion criteria
• histologically confirmed
prostate cancer
• bone metastasis
• failure of at least one
hormonal therapy
• ECOG: 0~2
• creatinine clearance ≧ 30
mL/min
• Zoledronic acid group
– 152 patients (17.3%) with creatinine clearance <
60ml/min  intial dose adjustment
– 78 patients (8.9%), total 344 doses were withheld due
to elevated serum creatinine
• No dose adjustments or dose withholding for
renal function for denosumab
• Renal AEs in patients with CCr < 60 ml/min
– n = 162 in zoledronic acid: 21.6%
– n = 151 in denosumab: 11.3%
• Inclusion criteria
– Histologic or cytologic confirmation of cancer, ≧ 18
y/o
– Severe HCM ( ≧ 12 mg/dL)
• Exclusion criteria
– Recent treatment with BPs
– Serum creatinine > 4.5 mg/dL
• Treatment
– Zoledronic acid 4 or 8 mg ( 5-minute IV infusion)
– Pamidronate 90 mg (2-hour IV infusion)
CR: CSC to ≦ 2.70 mmol/L (10.8 mg/dL) by day 10
A single-arm multicenter proof-of-concept study of denosumab
to treat hypercalcemia of malignancy in patients who are
refractory to IV bisphosphonates
• Background
– Refractory to BPs
– BPs are not recommended in severe renal impairment
– Animal models
• More effectively in Inhibition of RANK ligand (RANKL) than
high dose BPs
– Bone resorption
– Reversed established hypercalcemia
– Denosumab
• a fully human monoclonal antibody against RANKL
• approved from FDA for skeletal-related events in patients
with bone metastases from solid tumors
• Not interfere with renal function
• Methods
– Cancer, recent IV BP treatment ( 30 to 7 days prior),
corrected serum calcium (CSC) level > 12.5 mg/dL
– Exclusion: hyperparathyroidism, hyperthyroidism, adrenal
insufficiency or dialysis
– Denosumab 120 mg SC monthly
– Primary endpoint: proportion of patients with a response
 CSC ≤ 11.5 mg/dL by day 10 of treatment
– Secondary endpoints
•
•
•
•
Complete response ( CSC ≤ 10.8 mg/dL by day 10)
Time to response
Response duration
Safety
– Began enrolling patients in November 2009
– Total of 33 patients planned
18
serum total calcium
serum creatinine
16
14
(mg/dL)
12
10
8
6
4
2
0
0
normal saline
hydration
5
10
15
(Hospital day)
danosumab
120mg injection
20
25
Conclusion
• Denosumab, a fully human monoclonal
antibody for RANKL is a potent bone
resorption inhibitor
• The FDA-approved label for denosumab does
not specify a need for dose adjustment for
renal safety