Denosumab in bone metastasis of cancer and hypercalemia

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 • CCr30~60 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 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 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 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

42. Thanks your attention!