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;22:403–4122. 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– Fracture– Spinal cord compression – Hypercalcemia

(radiation or surgery treatment)

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

(Hospital day)

0 5 10 15 20 25

(mg/

dL)

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18serum total calcium serum creatinine

normal salinehydration

danosumab120mg injection

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

Thanks your attention!