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Bone metastases frequently have devastating consequences

SREs can be serious and debilitating^1-3

SREs are defined as³:

With increase in overall survival for patients with advanced cancer, patients are more likely to experience an SRE

Median time to first SRE vs median overall survival

*Median time to first SRE based on data from the placebo arms of 3 IV bisphosphonate pivotal trials (breast: pamidronate vs placebo; prostate and lung/other solid tumors: zoledronic acid vs placebo) in patients with metastatic cancer involving bone.^12,14,16
^†Median survival based on 3 publications of randomized, controlled trials (RCTs) each evaluating survival rates per tumor type, based on current therapeutic regimens. Patients on concurrent bisphosphonate therapy were not excluded and all patient groups included some percentage of patients with bone metastases.^13,15,17

All patients untreated for bone metastases are at risk of SREs, regardless of pain

In a retrospective analysis, the same percentage of patients without pain experienced one or more SREs compared to patients with pain (nearly 50% in each group)^18,19

Percentage of patients experiencing an SRE [pain vs no pain at baseline]^18,19

Data from the placebo arm (n = 208) of a retrospective analysis evaluating the efficacy of an IV bisphosphonate in the reduction of SREs and pain in men with bone metastases from prostate cancer.¹⁸

When not treated with a bone-targeting agent, patients with bone metastases may experience as many as 3.7 SREs per year^‡

Annual rate of SREs in untreated patients

Annual number of SREs in untreated patients

^‡Annual incidence of SREs based on data from the placebo arms of 3 IV bisphosphonate pivotal trials (breast: pamidronate vs placebo; prostate and lung/other solid tumors: zoledronic acid vs placebo) in patients with metastatic cancer involving bone.^3,12,16

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References

Roodman GD. Mechanisms of bone metastasis. N Engl J Med. 2004;350:1655-1664.
Mundy GR. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer. 2002;2:584-593.
Saad F, Gleason DM, Murray R, et al; Zoledronic Acid Prostate Cancer Study Group. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst. 2004;96:879-882.
Bradley NM, Husted J, Sey MS, et al. Review of patterns of practice and patients' preferences in the treatment of bone metastases with palliative radiotherapy. Support Care Cancer. 2007;15:373-385.
Mercadante S. Malignant bone pain: pathophysiology and treatment. Pain. 1997;69:1-18.
Tubiana-Hulin M. Incidence, prevalence and distribution of bone metastases. Bone. 1991;12(suppl 1):S9-S10.
Moore RE, Lackman RD. Metastatic bone disease. UPOJ. 2010;20:117-120.
Wedin R. Surgical treatment for pathologic fracture. Acta Orthop Scand Suppl. 2001;72:1-29.
Torbert JT, Lackman RD. Pathologic fractures. In: Pignolo RJ, Keenan MA, Hebela NM, eds. Fractures in the Elderly: A Guide to Practical Management. 1st ed. New York, NY: Springer Science and Business Media; 2011:43-53.
Nielsen OS, Munro AJ, Tannock IF. Bone metastases: pathophysiology and management policy. J Clin Oncol. 1991;9:509-524.
Osborn JL, Getzenberg RH, Trump DL. Spinal cord compression in prostate cancer. J Neurooncol. 1995;23:135-147.
Lipton A, Theriault RL, Hortobagyi GN, et al. Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases: a long term follow-up of two randomized, placebo controlled trials. Cancer. 2000;88:1082-1090.
Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007;357:2666-2676.
Saad F, Gleason DM, Murray R, et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst. 2002;94:1458-1468.
Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422.
Rosen LS, Gordon D, Tchekmedyian NS, et al. Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with nonsmall cell lung carcinoma and other solid tumors. Cancer. 2004;100:2613-2621.
Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355:2542-2550.
Saad F, Eastham J. Zoledronic acid improves clinical outcomes when administered before onset of bone pain in patients with prostate cancer. Urology. 2010;76:1175-1181.
Major P. Optimal management of metastatic bone disease. Eur J Oncol Nurs. 2007;11(suppl 2):S32-S37.

Full Prescribing Information | Amgen MedInfo | Contact Us

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Xgeva^® is not indicated for the prevention of skeletal-related events in patients with multiple myeloma.

Breast cancer: 18% risk reduction
in first SRE vs zoledronic acid^3,6 (P = 0.010, superiority)

Breast Cancer Study: Time to First SRE

^§P value for superiority.

Important Safety Information

Xgeva^® can cause severe hypocalcemia. Osteonecrosis of the jaw (ONJ) can occur in patients receiving Xgeva^®. The most common serious adverse reaction in patients receiving Xgeva^® was dyspnea.

Breast Cancer Study: Baseline Characteristics

	Xgeva^®(n = 1,026)	zoledronic acid(n = 1,020)
Median age	57 yrs	56 yrs
ECOG* status 0-1	93%	92%
Creatinine clearance ≤ 60 mL/min	12%	11%
Presence of visceral metastases	54%	51%
Prior SRE	37%	37%
> 2 bone metastases	24%	24%

*Eastern Cooperative Oncology Group.

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Xgeva^® is not indicated for the prevention of skeletal-related events in patients with multiple myeloma.

Prostate cancer: 18% risk reduction
in first SRE vs zoledronic acid^3,9 (P = 0.008, superiority)

Prostate Cancer Study: Time to First SRE

^§P value for superiority.

Important Safety Information

Xgeva^® can cause severe hypocalcemia. Osteonecrosis of the jaw (ONJ) can occur in patients receiving Xgeva^®. The most common serious adverse reaction in patients receiving Xgeva^® was dyspnea.

Prostate Cancer Study: Baseline characteristics

	Xgeva^®(n=950)	zoledronic acid(n=951)
Median age	71 yrs	71 yrs
ECOG* status 0-1	93%	93%
Creatinine clearance ≤ 60 mL/min	24%	22%
Presence of visceral metastases	17%	19%
Prior SRE	24%	24%
> 2 bone metastases	34%	35%

*Eastern Cooperative Oncology Group.

View Study Design

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Xgeva^® is indicated for the prevention of skeletal-related events (SREs) in patients with bone metastases from solid tumors.

Xgeva^® is not indicated for the prevention of skeletal-related events in patients with multiple myeloma.

Other solid tumors^‡/multiple myeloma: 16% risk reduction in first SRE vs zoledronic acid^3,8 (P < 0.001, noninferiority; P = 0.060, NS for superiority)

Subanalysis of other solid tumors^‡: 19% vs zoledronic acid^1,7 (P = 0.034, superiority)

Other Solid Tumors^‡/Multiple Myeloma Study: Time to First SRE

^‡Excluding breast and prostate cancer.

Important Safety Information

Xgeva^® can cause severe hypocalcemia. Osteonecrosis of the jaw (ONJ) can occur in patients receiving Xgeva^®. The most common serious adverse reaction in patients receiving Xgeva^® was dyspnea.

Other Solid Tumors/Multiple Myeloma Study: Baseline characteristics^3,8

BASELINE CHARACTERISTICS	Xgeva^®(n=886)	ZOLEDRONIC ACID(n=890)
Male	66%	62%
Median age	60 yrs	61 yrs
ECOG status 0-1	84%	82%
Median time from initial diagnosis of bone metastasis to randomization	2.0 mos	2.0 mos
Presence of visceral metastases	54%	50%
Prior SRE^§	50%	50%
Creatinine clearance ≤ 60 mL/min	17%	18%
Primary tumor type^\|\|
Non-small cell lung cancer	39%	40%
Multiple myeloma	10%	10%
Renal cell carcinoma	8%	10%
Small cell lung cancer	7%	5%
Other	36%	35%
Prior antineoplastic treatment	95%	96%
Systemic anticancer therapy	87%	87%
Radiotherapy	37%	40%
Surgery	46%	46%
Other	2%	2%

ECOG = Eastern Cooperative Oncology Group.
^§Randomization was stratified by prior SRE, systemic anticancer therapy at time of randomization, and tumor type (non-small cell lung cancer, multiple myeloma, or other).
^||A total of 40% of patients had non-small cell lung cancer, 10% had multiple myeloma, 9% had renal cell carcinoma, and 6% had small cell lung cancer. Other tumor types each comprised less than 5% of the enrolled population. Bladder cancer, rectal cancer, colon cancer, and other cancers (eg, head and neck, cervical, gastric, non-Hodgkin lymphoma, soft tissue sarcoma, endometrial, esophageal, neuroendocrine/carcinoid, melanoma, ovarian, thyroid, pancreatic) accounted for the remaining percentage of tumor types.^1,2

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XGEVA^® (denosumab): Head-to-Head Study of Patients with Breast Cancer

Study design¹

An international, phase 3, randomized, double-blind, active-controlled study comparing XGEVA^® with zoledronic acid for the prevention of skeletal-related events (SREs) in patients with bone metastases from advanced breast cancer¹
Per protocol and zoledronic acid label, the intravenous (IV) product was dose-adjusted for baseline creatinine clearance and subsequent dose intervals were determined by serum creatinine. No dose adjustments were made for increased serum creatinine for the subcutaneous (SC) product^1,2

Study endpoints¹

Primary Endpoint: Time to first on-study skeletal-related event (SRE) (noninferiority)

Study schema¹

XGEVA® (denosumab): Head-to-head Study of Patients with Breast Cancer study schema

Zoledronic acid 4 mg was administered as an IV infusion over a minimum of 15 minutes, once every 4 weeks, in accordance with prescribing information, with dose adjustments for renal function at baseline using the Cockcroft-Gault formula. Doses were withheld for any patient who experienced renal deterioration until recovery to within 10% of the baseline creatinine value.^1,2

XGEVA^® was administered subcutaneously 120 mg, once every 4 weeks.¹

Select exclusion criteria: patients receiving current or prior IV bisphosphonate therapy were excluded from the study. Patients receiving oral bisphosphonates for the treatment of osteoporosis were not excluded.²

*Daily supplementation of calcium ≥ 500 mg and vitamin D ≥ 400 IU was recommended.^1,2

Important Safety Information

XGEVA^® is contraindicated in patients with clinically significant hypersensitivity to any component of the product. XGEVA^® can cause severe symptomatic hypocalcemia, and fatal cases have been reported. Osteonecrosis of the jaw (ONJ) and atypical femoral fracture have been reported. XGEVA^® can cause fetal harm when administered to a pregnant woman.

Baseline characteristics^2,3

Baseline characteristics	XGEVA^® (denosumab) (n = 1,026)	zoledronic acid (n = 1,020)
Median age	57 yrs	56 yrs
ECOG^† status 0–1	93%	92%
Creatinine clearance ≤ 60 mL/min	12%	11%
Presence of visceral metastases	54%	51%
Prior SRE	37%	37%
> 2 bone metastases	24%	24%

^†Eastern Cooperative Oncology Group.

References

Xgeva^® (denosumab) prescribing information, Amgen.
Stopeck AT, Lipton A, Body J-J, et al; 20050136 Breast Cancer SRE Study Investigators. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol. 2010;28:5132-5139.
Data on file, Amgen.

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Thank you

Bone metastases frequently have devastating consequences

SREs can be serious and debilitating1-3

SREs are defined as3:

With increase in overall survival for patients with advanced cancer, patients are more likely to experience an SRE

Median time to first SRE vs median overall survival

All patients untreated for bone metastases are at risk of SREs, regardless of pain

Percentage of patients experiencing an SRE [pain vs no pain at baseline]18,19

When not treated with a bone-targeting agent, patients with bone metastases may experience as many as 3.7 SREs per year‡

Annual rate of SREs in untreated patients

References

Contact Us

Xgeva®: Superior efficacy across multiple solid tumor types

Time to first SRE in a prespecified integrated analysis of the 3 head-to-head studies1,2

Important Safety Information

Breast cancer: 18% risk reduction in first SRE vs zoledronic acid3,6 (P = 0.010, superiority)

Breast Cancer Study: Time to First SRE

Important Safety Information

Breast Cancer Study: Baseline Characteristics

Prostate cancer: 18% risk reduction in first SRE vs zoledronic acid3,9 (P = 0.008, superiority)

Prostate Cancer Study: Time to First SRE

Important Safety Information

Prostate Cancer Study: Baseline characteristics

Other solid tumors‡/multiple myeloma: 16% risk reduction in first SRE vs zoledronic acid3,8 (P < 0.001, noninferiority; P = 0.060, NS for superiority)

Subanalysis of other solid tumors‡: 19% vs zoledronic acid1,7 (P = 0.034, superiority)

Other Solid Tumors‡/Multiple Myeloma Study: Time to First SRE

Important Safety Information

Other Solid Tumors/Multiple Myeloma Study: Baseline characteristics3,8

Xgeva®: Superior efficacy across multiple solid tumor types

Reduced the risk of first SRE in 3 individual studies including more than 50 solid tumor types

Time to first SRE across 3 individual studies

Important Safety Information

XGEVA® (denosumab): Head-to-Head Study of Patients with Breast Cancer

Study design1

Study endpoints1

Study schema1

Important Safety Information

Baseline characteristics2,3

References

SREs can be serious and debilitating^1-3

SREs are defined as³:

Percentage of patients experiencing an SRE [pain vs no pain at baseline]^18,19

When not treated with a bone-targeting agent, patients with bone metastases may experience as many as 3.7 SREs per year^‡

Xgeva^®: Superior efficacy across multiple solid tumor types

Time to first SRE in a prespecified integrated analysis of the 3 head-to-head studies^1,2

Breast cancer: 18% risk reduction
in first SRE vs zoledronic acid^3,6 (P = 0.010, superiority)

Prostate cancer: 18% risk reduction
in first SRE vs zoledronic acid^3,9 (P = 0.008, superiority)

Other solid tumors^‡/multiple myeloma: 16% risk reduction in first SRE vs zoledronic acid^3,8 (P < 0.001, noninferiority; P = 0.060, NS for superiority)

Subanalysis of other solid tumors^‡: 19% vs zoledronic acid^1,7 (P = 0.034, superiority)

Other Solid Tumors^‡/Multiple Myeloma Study: Time to First SRE

Other Solid Tumors/Multiple Myeloma Study: Baseline characteristics^3,8

Xgeva^®: Superior efficacy across multiple solid tumor types

XGEVA^® (denosumab): Head-to-Head Study of Patients with Breast Cancer

Study design¹

Study endpoints¹

Study schema¹

Baseline characteristics^2,3