Coverage Policy Manual
Policy #: 2017009
Category: Pharmacy
Initiated: March 2017
Last Review: November 2018
  Denosumab (XGEVA™ and Prolia™)

Description:
Denosumab is a human monoclonal antibody acting as  an osteoclast inhibitor by  binding  to RANKL, a transmembrane or soluble protein essential for the formation, function, and survival of osteoclasts, thereby inhibiting bone resorption. This human monoclonal antibody prevents RANKL from activating its receptor, RANK, on the surface of osteoclasts and their precursors.  
 
Denosumab is marketed under the trade name XGEVA™ for the prevention of skeletal-related events in cancer patients with bone metastases from solid tumors and for treatment of adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity. XGEVA™ is also indicated for the treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy. XGEVA™ is supplied as an injection of 120 mg denosumab/1.7 mL (70 mg/mL) solution in a single-use vial for subcutaneous injection.
 
The same drug is marketed under the trade name Prolia™ for postmenopausal osteoporosis and as treatment to increase bone mass in patients with prostate and breast cancer who are on hormone ablation therapy. Prolia™ is supplied as a single-use prefilled syringe containing 60 mg denosumab in a 1 mL solution for subcutaneous injection.
 
Regulatory Status
The FDA approved denosumab under the brand name Prolia for the treatment of postmenopausal women with osteoporosis at high risk for fracture in June 2010. In September 2011, Prolia received FDA approval for osteoporosis prophylaxis in women at high risk for bone fractures after receiving adjuvant aromatase inhibitor therapy for breast cancer and in men at high risk for bone fractures after receiving androgen deprivation therapy for nonmetastatic prostate cancer. Then in September 2012, the FDA expanded the osteoporosis indication to include treatment of any man at high risk for fractures. The Xgeva brand was approved for the prevention of skeletal-related events in patients with bone metastases from solid tumors in November 2010. ((U.S. Food and Drug Administration, 2010, 2011, 2012).

Policy/
Coverage:
Effective November 2018
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage
Criteria
 
The use of denosumab meets primary coverage criteria in the treatment of the following listed indications when given subcutaneously and according to specified dosing guidelines for the indication:
 
Osteoporosis, Bone Mass Indications:
 
    • Prevention of fractures in men and women who have failed or cannot tolerate an oral biphosphonate. when one of the following criteria are met:
 
      • Member has osteoporosis (a pretreatment T-score of ≤- 2.5) OR
      • Member has osteopenia (a pre-treatment T-score between -1 and -2.5) and one of the following:
          • FRAX 10-year fracture probability ≥20% or FRAX hip fracture probability ≥3%  
 (* FRAX calculator can be found at : http://www.shef.ac.uk/FRAX/tool.jsp )
    • Prevention of osteoporosis in persons receiving aromatase inhibitors (anastrozole, letrozole, exemestane)
    • Treatment of glucocorticoid-induced osteoporosis in men and women at high risk* of fracture who are either initiating or continuing systemic glucocorticoids in a daily dosage equivalent to 7.5 mg or greater of prednisone and expected to remain on glucocorticoids for at least 6 months.   
    • Treatment to increase bone mass in men at high risk for fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer
 
* High risk of fracture is defined as a history of osteoporotic fracture, multiple risk factors for fracture, or patient who have failed or are intolerant to other available osteoporosis therapy.
 
Oncologic Indications:
 
1. Supportive therapy and prevention of skeletal-related events (SREs)* in patients with Bone Metastases from Solid Tumors (excluding prostate cancer unless castration resistant/recurrent) including but not limited to:
      • Breast Cancer,
      • Renal Cell Carcinoma,
      • Non-Small Cell Lung Cancer (NSCLC),
      • Castration-resistant Prostate Cancer, [osteoclast inhibition (with bisphosphonates or denosumab) does not significantly decrease the rate of skeletal-related events in men with hormone-sensitive metastatic disease],
      • Thyroid Cancer (Follicular, Hürthle Cell, Medullary, or Papillary Carcinomas).
 
2.  Supportive therapy and prevention of skeletal-related events (SREs)* in patients with multiple
myeloma.
 
3. Treatment of adults and skeletally mature adolescents with Giant Cell Tumor of bone that is
unresectable or where surgical resection is likely to result in severe morbidity, either:
      • as a single agent or in combination with interferon alfa or radiation therapy for localized disease; OR           
      • as a single agent for metastatic disease.
 
4. Treatment of Hypercalcemia of Malignancy refractory to bisphosphonate therapy.
 
 
 
*Note: For patients in whom an osteoclast inhibitor is indicated, a dental exam should be performed prior to treatment, preexisting hypocalcemia and/or vitamin D deficiency should be corrected prior to treatment, and patients counseled regarding adequate intake of calcium and vitamin D during therapy, unless contraindicated. Renal function should be evaluated prior to dosing both denosumab and biphosphonates.
 
Skeletal-related events (SREs) are defined as a pathologic fracture, spinal cord compression,
necessity for radiation to bone (for severe pain or impending fracture) or surgery to bone that are a
common complication of bone metastases.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary
Coverage Criteria
 
Any other use of denosumab does not meet member benefit certificate primary coverage criteria.
 
For members with contracts without primary coverage criteria, any other use of denosumab is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective Prior to November 2018
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage
Criteria
 
The use of denosumab meets primary coverage criteria in the treatment of the following listed
indications when given subcutaneously and according to specified dosing guidelines for the indication:
 
Osteoporosis, Bone Mass Indications:
 
  • Prevention of fractures in men and women who have failed or cannot tolerate an oral biphosphonate. when one of the following criteria are met:
      • Member has  osteoporosis (a pretreatment T-score of ≤- 2.5) OR
      • Member has osteopenia (a pre-treatment T-score between -1 and -2.5) and one of the following:
          • FRAX 10-year fracture probability ≥20% or FRAX hip fracture probability ≥3%
 
* FRAX calculator can be found at : http://www.shef.ac.uk/FRAX/tool.jsp
 
  • Prevention of osteoporosis in persons receiving aromatase inhibitors (anastrozole, letrozole, exemestane)
 
  • Treatment of glucocorticoid-induced osteoporosis in men and women at high risk of fracture who are either initiating or continuing systemic glucocorticoids in a daily dosage equivalent to 7.5 mg or greater of prednisone and expected to remain on glucocorticoids for at least 6 months.
 
* High risk of fracture is defined as a history of osteoporotic fracture, multiple risk factors for fracture, or patient who have failed or are intolerant to other available osteoporosis therapy.
 
  • Treatment to increase bone mass in men at high risk for fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer
 
Oncologic Indications:
1. Supportive therapy and prevention of skeletal-related events (SREs)* in patients with Bone
Metastases from Solid Tumors including:
    • Breast Cancer,
    • Renal Cell Carcinoma,
    • Non-Small Cell Lung Cancer (NSCLC),
    • Castration-resistant Prostate Cancer, [osteoclast inhibition (with bisphosphonates or
              denosumab) does not significantly decrease the rate of skeletal-related events in men with
              hormone-sensitive metastatic disease],
    • Thyroid Cancer (Follicular, Hürthle Cell, Medullary, or Papillary Carcinomas).
 
2. Treatment of adults and skeletally mature adolescents with Giant Cell Tumor of bone that is
unresectable or where surgical resection is likely to result in severe morbidity, either:
    • as a single agent or in combination with interferon alfa or radiation therapy for localized disease;
              OR
    • as a single agent for metastatic disease.
3. Treatment of Hypercalcemia of Malignancy refractory to bisphosphonate therapy.
4. Prevention of skeletal-related events in patients with multiple myeloma with chronic renal insufficiency, not on dialysis, with creatinine clearance of <90ml/min.
 
*Note: For patients in whom an osteoclast inhibitor is indicated, a dental exam should be performed prior to treatment, preexisting hypocalcemia and/or vitamin D deficiency should be corrected prior to treatment, and patients counseled regarding adequate intake of calcium and vitamin D during therapy, unless contraindicated. Renal function should be evaluated prior to dosing both denosumab and biphosphonates.
 
Skeletal-related events (SREs) are defined as a pathologic fracture, spinal cord compression,
necessity for radiation to bone (for severe pain or impending fracture) or surgery to bone that are a
common complication of bone metastases.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary
Coverage Criteria
 
Any other use of denosumab does not meet member benefit certificate primary coverage criteria.
 
For members with contracts without primary coverage criteria, any other use of denosumab is
considered investigational. Investigational services are specific contract exclusions in most member
benefit certificates of coverage.
 
Effective Prior to May 2018
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
The use of denosumab meets primary coverage criteria in the treatment of the following listed indications when given subcutaneously and according to specified dosing guidelines for the indication:
 
 
Osteoporosis, Bone Mass Indications:   
 
    • Prevention or Treatment of men and postmenopausal women with osteoporosis with a previous osteoporotic fracture or have multiple risk factors for fracture AND have failed or cannot tolerate an oral biphosphonate.
    • Prevention of osteoporosis in persons receiving aromatase inhibitors (anastrozole, letrozole, exemestane)
    • Treatment to increase bone mass in men at high risk for fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer
 
 
Oncologic Indications:
    1. Supportive therapy and prevention of skeletal-related events (SREs)* in patients with Bone Metastases from Solid Tumors including:  
 
      • Breast Cancer,
      • Renal Cell Carcinoma,
      • Non-Small Cell Lung Cancer (NSCLC),
      • Castration-resistant Prostate Cancer, [osteoclast inhibition (with bisphosphonates or denosumab) does not significantly decrease the rate of skeletal-related events in men with hormone-sensitive metastatic disease]
      • Thyroid Cancer (Follicular, Hürthle Cell, Medullary, or Papillary Carcinomas),
 
2. Treatment of adults and skeletally mature adolescents with Giant Cell Tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity, either:
      • as a single agent or in combination with interferon alfa or radiation therapy for localized disease; OR  
      • as a single agent for metastatic disease.
 
 
3.  Treatment of Hypercalcemia of Malignancy refractory to bisphosphonate therapy.
 
 
*Note:  For patients in whom an osteoclast inhibitor is indicated, a dental exam should be performed prior to treatment, preexisting hypocalcemia and/or vitamin D deficiency should be corrected prior to treatment, and patients counseled regarding adequate intake of calcium and vitamin D during therapy, unless contraindicated. Renal function should be evaluated prior to dosing both denosumab and biphosphonates.
 
Skeletal-related events (SREs) are defined as a pathologic fracture, spinal cord compression, necessity for radiation to bone (for severe pain or impending fracture) or surgery to bone that are a common complication of bone metastases.
 
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Other uses of denosumab do not meet member benefit certificate primary coverage criteria including, but not limited to:
    • Prevention of skeletal-related events in patients with multiple myeloma.
 
 
For members with contracts without primary coverage criteria, other uses of denosumab are considered investigational including, but not limited to:
    • Prevention of skeletal-related events in patients with multiple myeloma.
 
 
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
 
 
Dosing:
Denosumab is intended for subcutaneous route only and should not be administered intravenously, intramuscularly, or intradermally.
 
Bone Metastasis from Solid Tumors: Administer 120 mg every 4 weeks as a subcutaneous injection in the upper arm, upper thigh, or abdomen
 
Giant Cell Tumor of Bone: Administer 120 mg every 4 weeks with additional 120 mg doses on Days 8 and 15 of the first month of therapy. Administer subcutaneously in the upper arm, upper thigh, or abdomen.  Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia.
 
Hypercalcemia of Malignancy: Administer 120 mg every 4 weeks with additional 120 mg doses on Days 8 and 15 of the first month of therapy. Administer subcutaneously in the upper arm, upper thigh, or abdomen.
 
Osteoporosis:  Administer 60 mg every 6 months as a subcutaneous injection in the upper arm, upper thigh, or abdomen. Instruct patients to take calcium 1000 mg daily and at least 400 IU vitamin D daily.

Rationale:
Skeletal-related events (SREs) are a common complication of bone metastases and have serious negative consequences such as severe pain and reduced quality of life.  SREs are defined as a pathologic fracture, spinal cord compression, necessity for radiation to bone (for severe pain or impending fracture) or surgery to bone (Coleman, 1997; So et al, 2012; Gralow et al, 2013).
 
In 2011, an expert panel of the American Society of Clinical Oncology (ASCO) published the findings of a systematic review and update on their clinical practice guidelines on the role of bone-modifying agents in the prevention and treatment of skeletal-related events (SREs) for patients with metastatic breast cancer with bone metastases (Van Poznak et al on behalf of ESMO, 2011).  The society’s executive committee performed a literature review of all the relevant studies published between January 2003 and November 2010.  The primary outcomes were SREs and time to SRE. Secondary outcomes were adverse events and pain.  
 
The ASCO key recommendations are as follows:  
    • BMAs are recommended for patients with metastatic breast cancer with evidence of bone destruction.
    • Denosumab, 120 mg subcutaneously every 4 weeks; intravenous (IV) pamidronate, 90 mg over no less than 2 hours every 3 to 4 weeks; or IV zoledronic acid, 4 mg over no less than 15 minutes every 3 to 4 weeks.
    • One BMA is not recommended over another.
    • In patients with creatinine clearance > 60 mL/min, no change in dosage, infusion time or interval is required; monitor creatinine level with each IV bisphosphonate dose.
    • In patients with creatinine clearance < 30 mL/min or on dialysis who may be treated with denosumab, close monitoring for hypocalcemia is recommended.
    • All patients should have a dental exam and preventive dentistry before receiving a BMA.
    • At onset of cancer bone pain, provide standard of care for pain management and start BMAs.
    • Use of biochemical markers to monitor BMA use is not recommended for routine care.
 
 
In 2012, Martin et al published the results of a randomized control trial comparing the use of denosumab versus zoledronic acid in the treatment of advanced breast cancer.  The study enrolled and randomly assigned 2,046 patients 1:1 to receive either subcutaneous denosumab 120 mg (n = 1,026) and intravenous placebo, or intravenous zoledronic acid 4 mg (n = 1,020) and subcutaneous placebo every 4 weeks. The primary and secondary endpoints were the proportion of patients with one or multiple on-study SREs, Other outcomes analyzed included time to first radiation to bone, time to first SRE or hypercalcemia of malignancy, and change in general health-related quality of life (HRQoL). The results were as follows.  Fewer patients receiving denosumab than zoledronic acid had an on-study SRE (31% vs. 36%). The incidence of first radiation to bone was 12% with denosumab versus 16% with zoledronic acid. Denosumab prolonged the time to first radiation to bone by 26% versus zoledronic acid and prolonged the time to first SRE or hypercalcemia of malignancy by 18%. Ten percent more patients had a clinically meaningful improvement in HRQoL with denosumab relative to zoledronic acid, regardless of baseline pain levels. The authors concluded that denosumab was superior to zoledronic acid in reducing bone-related complications of metastatic breast cancer and maintained health-related quality of life.  Denosumab provides an efficacious, well-tolerated treatment option for patients with bone metastases from breast cancer.
 
In 2012, Vadhan-Raj et al also published the results of a randomized, international double-blind, double-dummy phase 3 trial comparing the efficacy and safety of denosumab and zoledronic acid.  The study randomly assigned 1,776 patients with advanced solid tumor cancer (excluding breast and prostate cancer) or multiple myeloma to either treatment with denosumab (n=886) or zoledronic acid (n=890). The primary end points of the study included time to first on-study SRE or hypercalcemia of malignancy, time to first radiation to bone; skeletal morbidity rate (SMR) analgesic use pain severity, and health related quality of life (FACT-G) scores.  The results of the study were that denosumab compared to zoledronic acid reduced the risk of radiation to bone by 22%, prevented worsening of pain and pain interference, and reduced the frequency of a shift from no/weak opioid analgesic use to strong opioids at months 3-5. Denosumab delayed the time to moderate-to-severe pain compared with zoledronic acid in patients with mild or no pain at the baseline (P = 0.04), supporting early treatment. Health-related quality-of-life scores were similar in both groups. The number of patient-years needed to treat to avoid one SRE for denosumab was 3 years versus placebo and 10 years versus zoledronic acid. The authors concluded that the use of denosumab was associated with better prevention of the complications of metastatic bone disease secondary to solid tumors or multiple myeloma compared to zoledronic acid.
 
2018 Update
In January 2018, the U.S. FDA approved the supplemental Biologics License Application (sBLA) for XGEVA® (denosumab) to expand the currently approved indication for the prevention of skeletal-related events in patients with bone metastases from solid tumors to include patients with multiple myeloma. The approval is based on data from the pivotal Phase 3 study (Raje, 2018). This study was the largest international multiple myeloma clinical trial ever conducted, which enrolled 1,718 patients.
 
In this Phase 3 trial, Raje et al randomized, a total of 1,718 patients (859 on each arm) to receive either subcutaneous XGEVA 120 mg and intravenous placebo every four weeks, or intravenous zoledronic acid 4 mg (adjusted for renal function) and subcutaneous placebo every four weeks (Raje, 2018). The primary endpoint of the study was non-inferiority of XGEVA versus zoledronic acid with respect to time to first on-study skeletal-related event (pathologic fracture, radiation to bone, surgery to bone or spinal cord compression). Secondary endpoints included superiority of XGEVA versus zoledronic acid with respect to time to first on-study skeletal-related event and first-and-subsequent on-study skeletal-related event and evaluation of overall survival. Progression-free survival was an exploratory endpoint. The safety and tolerability of XGEVA were also compared with zoledronic acid.
 
The study met the primary endpoint, demonstrating non-inferiority of XGEVA to zoledronic acid in delaying the time to first on-study skeletal-related event in patients with multiple myeloma (HR=0.98, 95 percent CI: 0.85, 1.14; p=0.01). The secondary endpoints, delaying time to first skeletal-related event and delaying time to first-and-subsequent skeletal-related events, did not demonstrate superiority. Overall survival was comparable between XGEVA and zoledronic acid, with a hazard ratio of 0.90 (95 percent CI: 0.70, 1.16; p=0.41). The median difference in progression-free survival favored XGEVA by 10.7 months (HR=0.82, 95 percent CI: 0.68-0.99; descriptive p=0.036). Median progression-free survival was 46.1 months (95 percent CI: 34.3 months, not estimable [NE], n=219) for XGEVA and 35.4 months (95 percent CI: 30.2 months, NE, n=260) for zoledronic acid.
 
Adverse events observed in patients treated with XGEVA were generally consistent with the known safety profile of XGEVA. The most common adverse reactions (greater than or equal to 10 percent) were diarrhea (34 percent), nausea (32 percent), anemia (22 percent), back pain (21 percent), thrombocytopenia (19 percent), peripheral edema (17 percent), hypocalcemia (16 percent), upper respiratory tract infection (15 percent), rash (14 percent) and headache (11 percent).  The most common adverse reaction resulting in discontinuation of XGEVA (greater than or equal to 1.0 percent) was osteonecrosis of the jaw (ONJ). In the primary treatment phase of the '482 study, ONJ was confirmed in 4.1 percent of patients in the XGEVA group (median exposure of 16 months; range: 1 - 50) and 2.8 percent of patients in the zoledronic acid group (median 15 months, range: 1 - 45 months).

CPT/HCPCS:
J0897Injection, denosumab, 1 mg

References: Amgen, Inc.(2016) Package Insert. Prolia (denosumab) solution for injection. Thousand Oaks, CA: Amgen, Inc.; 2016 Aug.

Amgen, Inc.(2016) Package Insert. Xgeva (denosumab) injection package insert. Thousand Oaks, CA: Amgen, Inc.; 2016 Mar.

Coleman, R. E.(1997) Skeletal complications of malignancy. Cancer, 80: 1588–1594. doi:10.1002/(SICI)1097-0142(19971015)80:8+<1588::AID-CNCR9>3.0.CO;2-G.

Gralow JR, Biermann JS, Farooki A, et al.(2013) NCCN Task Force report: bone health in cancer care. J Natl Compr Canc Netw. 2013;11(suppl 3):s1-s50.

Martin M, Bell R, Bourgeois H, Brufsky A, Diel I, Eniu A, Fallowfield L, Fujiwara Y, Jassem J, Paterson AH, Ritchie D, Steger GG, Stopeck A, Vogel C, Fan M, Jiang Q, Chung K, Dansey R, Braun A.(2012) Bone-related complications and quality of life in advanced breast cancer: results from a randomized phase III trial of denosumab versus zoledronic acid. Clin Cancer Res. 2012 Sep;18(17):4841-9. Epub 2012 Aug 14.

NCCN(2017) NCCN Compendia. https://www.nccn.org/professionals/drug_compendium/MatrixGenerator/Matrix.aspx?AID=5. Accessed February 10, 2017.

Raje N., Terpos E., Willenbacher W. et al.(2018) Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: an international, double-blind, double-dummy, randomised, controlled, phase 3 study. Lancet Oncol. 2018 Mar;19(3):370-381. Epub 2018 Feb 9.

So, A., Chin, J., Fleshner, N., and Saad, F.(2012) Management of skeletal-related events in patients with advanced prostate cancer and bone metastases: Incorporating new agents into clinical practice. Can Urol Assoc J. 2012 Dec; 6(6): 465–470. PMCID: PMC3526633.

Vadhan-Raj S, von Moos R, Fallowfield LJ, Patrick DL, Goldwasser F, Cleeland CS, Henry DH, Novello S, Hungria V, Qian Y, Feng A, Yeh H, Chung K.(2012) Clinical benefit in patients with metastatic bone disease: results of a phase 3 study of denosumab versus zoledronic acid. Ann Oncol. 2012;23(12):3045.

Van Poznak CH, Temin S, Yee GC, Janjan NA, Barlow WE, Biermann JS, Bosserman LD, Geoghegan C, Hillner BE, Theriault RL, Zuckerman DS, Von Roenn JH, American Society of Clinical Oncology.(2011) American Society of Clinical Oncology executive summary of the clinical practice guideline update on the role of bone-modifying agents in metastatic breast cancer. J Clin Oncol. 2011;29(9):1221.


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
CPT Codes Copyright © 2019 American Medical Association.