1. Denosumab in bone metastasis of cancer and hypercalemia Supervisor: 趙大中 大夫 Reporter: 郭政裕 總醫師

2. 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

3. 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 )

4. How to treat hypercalcemia of malignancy (HCM) ? – Vigorous saline hydration – Loop diuretic after volume expansion – Bisphosphonates (BPs) ?? Zoledronic acid Pamidronate

5. 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 ?

6. Zoledronate and acute renal failure Kidney International, Vol. 64 (2003), pp. 281–289, Markowitz et al

8. Bone resorption inhibitor: bisphosphate vs. denosumab Denosumab (FDA approval) – Osteoporosis – ↓ skeletal-related events of maliganancy with bone metastases – Hypercalcemia (X): ongoing trial

9. RANKL: receptor activator of neuclear factor kappa ligand: a essential signal to stimulate differentiation, activity and survival of osteoclast

11. Denosumab: a fully human monoclonal antibody to RANKL

13. 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

14. 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

16. Skeletal-related events – Pain – Fracture – Spinal cord compression – Hypercalcemia (radiation or surgery treatment)

17. Inclusion criteria: Adenocarcinoma of breast ≧ 18 y/o bone metastasis ECOG: 0~2 creatinine clearance ≧ 30 mL/min

21. Inclusion criteria solid tumor (except breast and prostate ) or multiple myeloma ≧ 18 y/o bone metastasis ECOG: 0~2 creatinine clearance ≧ 30 mL/min

25. Inclusion criteria histologically confirmed prostate cancer bone metastasis failure of at least one hormonal therapy ECOG: 0~2 creatinine clearance ≧ 30 mL/min

27. 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%

31. 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)

33. CR: CSC to ≦ 2.70 mmol/L (10.8 mg/dL) by day 10

38. 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

39. 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

41. 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