| Coverage Policy Manual | |
| Policy #: | 2017009 |
| Category: | Pharmacy |
| Initiated: | March 2017 |
| Last Review: | June 2024 |
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| Denosumab (e.g., XGEVA™ and Prolia™) | |
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| 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 individuals 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. Denosumab (e.g., XGEVA™) is also indicated for the treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy. Denosumab (e.g., 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 Denosumab (e.g., Prolia™) for postmenopausal osteoporosis and as treatment to increase bone mass in individuals 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 individuals with bone metastases from solid tumors in November 2010. ((U.S. Food and Drug Administration, 2010, 2011, 2012).
Coding
See CPT/HCPCS Code section below.
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Policy/ Coverage: |
Effective August 1, 2021, for members of plans that utilize an oncology benefits management program, Prior Approval is required for this service when rendered for oncologic indications and is managed through the oncology benefits management program.
Effective June 19, 2024
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Denosumab meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when all the following criteria are met:
FDA Labeled Indications:
For FDA labeled indications, all products must be dosed in accordance with the FDA label unless otherwise specified.
OSTEOPOROSIS, BONE MASS INDICATIONS for denosumab (e.g., Prolia):
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
CONTINUED APPROVAL for up to 12 months:
ONCOLOGIC INDICATIONS for denosumab (e.g., Xgeva):
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
CONTINUED APPROVAL for up to 12 months:
Off-label Indications:
For off-label indications, authorizations will not exceed 60 mg every 6 months for Prolia or 120 mg for Xgeva every 4 weeks for maintenance dosing (induction doses will be allowed as recommended by medical literature) OR maximum recommended doses as outlined in dosage and administration section.
STANDARD REVIEW for up to 12 months:
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1, or 2A, recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Policy Guidelines
High risk of fracture is defined as a history of osteoporotic fracture, multiple risk factors for fracture, or individual who have failed or are intolerant to other available osteoporosis therapy.
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.
*Note: For individuals 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 individuals counseled regarding adequate intake of calcium and vitamin D during therapy, unless contraindicated. Renal function should be evaluated prior to dosing both denosumab and bisphosphonates.
Dosage and Administration
Dosing per FDA Guidelines
Denosumab (e.g., Prolia)
For all conditions:
The recommended dosage is 60 mg every 6 months as a subcutaneous injection in the upper arm, upper thigh, or abdomen.
Denosumab (e.g., Prolia) is available as a single-dose prefilled syringe containing 60 mg in a 1 mL solution.
Denosumab (e.g., Prolia) should be administered as a subcutaneous injection by a healthcare professional.
Denosumab (e.g., Xgeva)
Denosumab (e.g., Xgeva) is available as 120 mg/1.7 mL (70 mg/mL) solution in a single-dose vial.
Denosumab (e.g., Xgeva) should be administered as a subcutaneous injection by a healthcare professional.
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Denosumab, for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, denosumab, for any indication or circumstance not described above, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective February 2024 to June 18, 2024
For FDA labeled indications, all products must be dosed in accordance with the FDA label unless otherwise specified.
For off-label indications, authorizations will not exceed 60 mg every 6 months for Prolia or 120 mg for Xgeva every 4 weeks for maintenance dosing (induction doses will be allowed as recommended by medical literature) OR maximum recommended doses as outlined in dosage and administration section.
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Denosumab meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes When all of the following are met:
OSTEOPOROSIS, BONE MASS INDICATIONS for denosumab (e.g., Prolia):
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
CONTINUED APPROVAL for up to 12 months:
ONCOLOGIC INDICATIONS for denosumab (e.g., Xgeva):
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
CONTINUED APPROVAL for up to 12 months:
OFF LABEL USE
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1, or 2A, recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Policy Guidelines
High risk of fracture is defined as a history of osteoporotic fracture, multiple risk factors for fracture, or individual who have failed or are intolerant to other available osteoporosis therapy.
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.
*Note: For individuals 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 individuals counseled regarding adequate intake of calcium and vitamin D during therapy, unless contraindicated. Renal function should be evaluated prior to dosing both denosumab and bisphosphonates.
Dosage and Administration
Dosing per FDA Guidelines
Denosumab (e.g., Prolia)
For all conditions:
The recommended dosage is 60 mg every 6 months as a subcutaneous injection in the upper arm, upper thigh, or abdomen.
Denosumab (e.g., Prolia) is available as a single-dose prefilled syringe containing 60 mg in a 1 mL solution.
Denosumab (e.g., Prolia) should be administered as a subcutaneous injection by a healthcare professional.
Denosumab (e.g., Xgeva)
1. Multiple Myeloma and Bone Metastasis from Solid Tumors:
The recommended dosage is 120 mg every 4 weeks as a subcutaneous injection in the upper arm, upper thigh, or abdomen.
2. Giant Cell Tumor of Bone:
The recommended dose is 120 mg every 4 weeks with additional 120 mg doses on Days 8 and 15 of the first month of therapy only. Administer subcutaneous in the upper arm, upper thigh, or abdomen.
3. Hypercalcemia of Malignancy:
The recommended is dose is 120 mg every 4 weeks with additional 120 mg doses on Days 8 and 15 of the first month of therapy only. Administer subcutaneously in the upper arm, upper thigh, or abdomen.
Denosumab (e.g., Xgeva) is available as 120 mg/1.7 mL (70 mg/mL) solution in a single-dose vial.
Denosumab (e.g., Xgeva) should be administered as a subcutaneous injection by a healthcare professional.
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
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 that there be scientific evidence of effectiveness.
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 June 7, 2023-January 31, 2024
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
The use of denosumab meets primary coverage criteria that there be scientific evidence of effectiveness in the treatment of the following listed indications when given subcutaneously and according to specified dosing guidelines for the indication:
Osteoporosis, Bone Mass Indications for denosumab (e.g., Prolia):
Continuation Request for denosumab (e.g., Prolia):
Approved if both of the following criteria are met:
Oncologic Indications for denosumab (e.g., Xgeva):
All oncologic indications for denosumab (e.g., Xgeva) require Prior Approval through the oncology benefits management program.
*Note: For individuals 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 individuals 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.
Off Label
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1, 2A, and 2B recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosage and Administration
Dosing per FDA Guidelines
Administer 60 mg every 6 months as a subcutaneous injection in the upper arm, upper thigh, or abdomen.
Instruct individuals to take calcium 1000 mg to take calcium 1000 mg daily and at least 400 IU vitamin D daily.
Denosumab (e.g., Xgeva) is available as a single-dose prefilled syringe containing 60 mg in a 1 mL solution.
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
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 that there be scientific evidence of effectiveness.
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 January 1, 2022 to June 6, 2023
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
The use of denosumab meets primary coverage criteria that there be scientific evidence of effectiveness in the treatment of the following listed indications when given subcutaneously and according to specified dosing guidelines for the indication:
Osteoporosis, Bone Mass Indications for denosumab (e.g., Prolia):
* 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.
Continuation Request for denosumab (e.g., Prolia):
Approved if both of the following criteria are met:
Oncologic Indications for denosumab (e.g., Xgeva):
All oncologic indications for denosumab (e.g., Xgeva) require Prior Approval through the oncology benefits management program.
*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.
Off Label
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1, 2A, and 2B recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosage and Administration
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
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 that there be scientific evidence of effectiveness.
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 November 1, 2021 to December 31, 2021
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:
* 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:
*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.
Off Label
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1, 2A, and 2B recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosage and Administration
Per FDA label guidelines.
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
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 November 2018 to October 31, 2021
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:
* 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:
*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:
* 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 including:
denosumab) does not significantly decrease the rate of skeletal-related events in men with
hormone-sensitive metastatic disease],
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:
OR
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:
Oncologic Indications:
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:
For members with contracts without primary coverage criteria, other uses of denosumab are considered investigational including, but not limited to:
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.
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| 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:
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).
2019 Update
The post-hoc analysis queried whether women experiencing fracture on denosumab indicates inadequate treatment response or whether the risk of subsequent fracture remains low with continuing denosumab. Results showed that denosumab decreases the risk of subsequent fracture and fracture sustained while on denosumab is not necessarily indicative of inadequate treatment response.
This analysis assessed whether a fracture sustained during denosumab therapy indicates inadequate treatment response and if the risk of a subsequent fracture decreases with continuing denosumab treatment.
In FREEDOM, a clinical trial to evaluate the efficacy and safety of denosumab, postmenopausal women with osteoporosis were randomized to placebo or denosumab for 3 years. In the 7-year FREEDOM Extension, all participants were allocated to receive denosumab. Subsequent osteoporotic fracture rates were compared between denosumab-treated subjects during FREEDOM or the Extension and placebo-treated subjects in FREEDOM.
During FREEDOM, 438 placebo- and 272 denosumab-treated subjects had an osteoporotic fracture. Exposure-adjusted subject incidence per 100 subject-years was lower for denosumab (6.7) vs placebo (10.1). Combining all subjects on denosumab from FREEDOM and the Extension for up to 10 years (combined denosumab), 794 (13.7%) had an osteoporotic fracture while on denosumab. Of these, one or more subsequent fractures occurred in 144 (18.1%) subjects, with an exposure-adjusted incidence of 5.8 per 100 subject-years, similar to FREEDOM denosumab (6.7 per 100 subject-years) and lower than FREEDOM placebo (10.1 per 100 subject-years). Adjusting for prior fracture, the risk of having a subsequent on-study osteoporotic fracture was lower in the combined denosumab group vs placebo (hazard ratio [95% CI]: 0.59 [0.43–0.81]; P = 0.0012).
These data demonstrate that denosumab decreases the risk of subsequent fracture and a fracture sustained while on denosumab is not necessarily indicative of inadequate treatment response. (Kendler, et. al., 2019)
2020 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2020. No new literature was identified that would prompt a change in the coverage statement.
2021 Update
Data from the phase 3 study of denosumab were used as an exemplar comparing the effects of active intervention with placebo on the risk of all fractures associated with osteoporosis. Fracture outcomes were assigned utility weights drawn from the published literature and applied to age-specific health state values of the general population. For each fracture outcome in each arm of the study, cumulative disutility was computed to serve as the principal end point. The hypothesis evaluated was that treatment with denosumab results in a significant reduction in mean fracture-related disutility.
Treatment with denosumab was associated with significantly lower utility loss compared with placebo. For patients treated with denosumab, mean utility loss was 42% less than with placebo (4.5 vs. 7.5 QALYs/1000 patient years, respectively, p < 0.001).
Denosumab significantly decreased utility loss. The use of metrics that combine fracture outcomes may provide added power to phase 3 studies and provide a surrogate outcome for regulatory agencies. (Kanis JA, Harvey NC, Lorentzon M, et. al., 2021)
The FREEDOM (Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months) trial showed denosumab significantly reduced the risk of fractures in postmenopausal women with osteoporosis.
The effect of denosumab on the incidence of new vertebral and hip fractures in subgroups of women at higher risk for these fractures was evaluated in a 3-yr, randomized, double-blind, placebo-controlled, phase 3 trial. Participants included postmenopausal women (N = 7808) with osteoporosis who were enrolled at 213 study sites worldwide. Subjects received s.c. denosumab (60 mg) or placebo every 6 months and daily supplements of calcium (≥1000 mg) and vitamin D (≥400 IU).
This post hoc analysis evaluated fracture incidence in women with known risk factors for fractures including multiple and/or moderate or severe prevalent vertebral fractures, aged 75 yr or older, and/or femoral neck bone mineral density T-score of -2.5 or less.
Compared with placebo, denosumab significantly reduced the risk of new vertebral fractures in women with multiple and/or severe prevalent vertebral fractures (16.6% placebo vs. 7.5% denosumab; P < 0.001). Similarly, denosumab significantly reduced the risk of hip fractures in subjects aged 75 yr or older (2.3% placebo vs. 0.9% denosumab; P < 0.01) or with a baseline femoral neck bone mineral density T-score of -2.5 or less (2.8% placebo vs. 1.4% denosumab; P = 0.02). These risk reductions in higher-risk individuals were consistent with those seen in patients at lower risk of fracture.
Denosumab reduced the incidence of new vertebral and hip fractures in postmenopausal women with osteoporosis at higher risk for fracture. These results highlight the consistent antifracture efficacy of denosumab in patients with varying degrees of fracture risk. (Boonen S, Adachi JD, Man Z, et. al., 2011)
2022 Update
According to Coleman R, Zhou Y, Jandial D, et.al. (2021), a denosumab study enrolled women (aged ≥ 18 years) with histologically confirmed stage II/III breast cancer. Patients treated with adjuvant/neoadjuvant chemotherapy meeting inclusion criteria were randomly assigned 1:1 to receive either denosumab (120 mg) or placebo subcutaneously every 3-4 weeks for about 6 months and then every 3 months for a total treatment duration of 5 years. Five prespecified exploratory bone endpoints and post hoc subgroup analysis based on age (< 50 and ≥ 50 years) and menopause status (premenopausal and postmenopausal) were evaluated.
Overall, 4509 women with early-stage breast cancer were assigned to receive denosumab (N = 2256) or placebo (N = 2253). The baseline demographics and clinical characteristics were comparable between the two arms. The hazard ratio (HR) for time to first bone metastasis was 0.82 (95% CI 0.66-1.02; p = 0.068), with HRs of 0.70 (95% CI 0.52-0.94; p = 0.018) for patients < 50 years old and 0.74 (95% CI 0.55-0.98; p = 0.038) for premenopausal patients, favoring the denosumab group. The HRs for time to first on-study fracture and time to first on-study skeletal-related event were 0.76 (95% CI 0.63-0.92; p = 0.004) and 0.52 (95% CI 0.35-0.78; p = 0.001), respectively, again favoring the denosumab group.
The exploratory bone endpoints indicate the benefits of denosumab treatment in patients with high-risk early breast cancer, supporting the expected bone health benefits contributed by denosumab.
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2023. No new literature was identified that would prompt a change in the coverage statement.
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2024. No new literature was identified that would prompt a change in the coverage statement.
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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. Bird ST, Smith ER, Gelperin K, Jung TH, Thompson A, Kambhampati R, Lyu H, Zhao H, Zhao Y, Zhu Y, Easley O.(2024) Severe Hypocalcemia With Denosumab Among Older Female Dialysis-Dependent Patients. JAMA. 2024 Jan 19. Boonen S, Adachi JD, Man Z, et. al.,(2011) Treatment with denosumab reduces the incidence of new vertebral and hip fractures in postmenopausal women at high risk. J Clin Endocrinol Metab. 2011 Jun;96(6):1727-36. doi: 10.1210/jc.2010-2784. Epub 2011 Mar 16. PMID: 21411557. Coleman R, Zhou Y, Jandial D, Cadieux B, Chan A.(2021) Bone Health Outcomes from the International, Multicenter, Randomized, Phase 3, Placebo-Controlled D-CARE Study Assessing Adjuvant Denosumab in Early Breast Cancer. Adv Ther. 2021 Aug;38(8):4569-4580. doi: 10.1007/s12325-021-01812-9. Epub 2021 Jun 29. PMID: 34185259; PMCID: PMC8342342. 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. Kanis JA, Harvey NC, Lorentzon M, et. al.,(2021) Combining fracture outcomes in phase 3 trials of osteoporosis: an analysis of the effects of denosumab in postmenopausal women. Osteoporos Int. 2021 Jan;32(1):165-171. doi: 10.1007/s00198-020-05699-0. Epub 2020 Nov 6. PMID: 33156354. Kendler, D. L., Chines, A., Brandi, M. L., Papapoulos, S., Lewiecki, E. M., Reginster, J. Y., … Bone, H. G.(2019) The risk of subsequent osteoporotic fractures is decreased in subjects experiencing fracture while on denosumab: results from the FREEDOM and FREEDOM Extension studies. Osteoporosis international: a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA, 30(1), 71–78. doi:10.1007/s00198-018-4687-2 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 Drugs & Biologics Compendium® for Denosumab, © National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed [January 30, 2024]. To view the most recent and complete version of the Compendium, go online to NCCN.org 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. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)(2023) for Prostate Cancer V 4.2023-September 7, 2023. © National Comprehensive Cancer Network, Inc. 2023. All rights reserved. Accessed January 30, 2024. To view the most recent and complete version of the guideline, go online to NCCN.org. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)(2024) for Breast Cancer V 1.2024-January 25, 2024. © National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed January 30, 2024. To view the most recent and complete version of the guideline, go online to NCCN.org. 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. |
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