Indication
XGEVA® is indicated for the prevention of skeletal‐related events in patients with multiple myeloma and in patients with bone metastases from solid tumors.
XGEVA® first vs step therapy additional information
MODEL SUMMARY1-8
*The average time on treatment in the model was 1.085 years in the XGEVA® first arm and 1.076 in the step therapy policy restricting XGEVA®. Average time to switch to XGEVA® weighted across tumor types was 6.3 months in the model.1
†Based on a retrospective study of electronic medical records from the OSCER database to identify adult solid tumor patients with first bone metastasis diagnosis between 1/1/12 and 12/31/14 (N=14,881).2
‡Adjusted by a real-world factor of 2.84, for both those on treatment and not on treatment, which was estimated from published literature.1
§As there was no difference in OS between XGEVA® and ZA in the clinical trial, OS data were pooled and extrapolated over the model time horizon. Median survival in the model was 1.69 years.1
**Based on Q3 2017 Average Selling Price.1
Key assumptions and limitations1
• Step through ZA to XGEVA® in the model is based only on the occurrence of a first SRE following treatment initiation
• To stay consistent with prior analyses evaluating the cost-effectiveness of XGEVA®, the SRE rates for XGEVA® were calculated using SRE rates for ZA from the three solid tumor phase 3 pivotal trials and applying efficacy. When XGEVA® rates from the trials were modeled in a scenario analysis, the incremental value delivered by XGEVA® improved by 3%, while the difference in total direct costs remained approximately 5%
• SRE costs in patients with other solid tumors were assumed to be the average of the costs in breast and prostate cancer
• The results should be interpreted within the context of the data inputs and modeling assumptions used as the results may be sensitive to changes in these inputs
• Costs of health services were estimated from multiple sources, which varied by tumor type, patient population, country, and other parameters
• The mortality rate was extrapolated to reflect a time horizon of 3 years, which may or may not accurately reflect actual outcomes
Financial disclosures
Model inputs
Clinical inputs
Clinical efficacy inputs – risk of first SRE for XGEVA®, ZA, and no treatment1,7
Estimate the probability of first SRE
Time to first SRE from the ZA arms of the pivotal phase 3 trials were used to estimate the probability of first SRE over time for each cancer type using parametric modeling. This probability changes per cycle as a result of the parametric modeling details.
Adjust probability of first SRE for real world occurrence*
The probability of first SRE for ZA per cycle was adjusted for real world occurrence by cancer type, according to the following equations:
• Prostate and Other Solid Tumors: Log Normal Distribution: Survival function (time to 1st SRE) for ZA =1 – {1-NORMDIST((LN((Cycle # +1) x 28 days)-Intercept)/Scale^(Real-World Adjustment Factor)
• Breast: Gamma distribution: Survival function (time to 1st SRE) for ZA = 1 – {GAMMADIST((Shape^-2) x EXP(Shape x ((LN((Cycle # +1) x 28 days)-Intercept)/Scale)),-Shape^-2)^(Real-World Adjustment Factor)
Estimate the probability of first SRE for XGEVA®
• The hazard ratio (HR) of XGEVA® vs ZA from the pivotal phase 3 trials was utilized and multiplied by the real world-adjusted rate of first SRE for ZA from Step 2:
Survival function (time to 1st SRE) for
XGEVA® = Survival function (time to 1st SRE) for ZA x HR (XGEVA® vs ZA)
*To better reflect SRE real-world rates, the clinical trial annual rates are adjusted for all treatments including the no-treatment arm. Annual SRE rates were extrapolated from real-world data. Based on real-world data, a conversion factor was applied to SRE rates from the Phase III clinical trials. The adjustment factor used was estimated to be 2.84.1 This value is multiplied by the crude annual SRE rate described above to estimate treatment-specific real-world SRE rates.
Clinical efficacy inputs – risk of subsequent SRE for XGEVA®, ZA, and no treatment1,9,10
Estimate subsequent SRE rates for patients experiencing a first SRE
After the first SRE, the model applies a SRE rate among patients with a prior SRE by cancer type.
ZA then XGEVA® subsequent SRE rate: Weighted average of the subsequent SRE rates from the clinical trial for ZA (patients who remain on ZA) and for XGEVA® (patients who switch to XGEVA®), and from a bisphosphonate vs placebo study for untreated patients (patients who discontinue).
XGEVA® first subsequent SRE rate: Weighted average of the subsequent SRE rate for XGEVA® from the clinical trial (for patients who remain on XGEVA®) and for untreated patients from a bisphosphonate vs placebo study (for patients who discontinue).
†To better reflect SRE real-world rates, the clinical trial annual rates are adjusted for all treatments including the no-treatment arm. Annual SRE rates were extrapolated from real-world data. Based on real-world data, a conversion factor was applied to the SRE rates from the Phase III clinical trials. The adjustment factor used was estimated to be 2.84.1 This value is multiplied by the crude annual SRE rate described above to estimate treatment-specific real-world SRE rates.
‡To estimate the no-treatment arm SRE rates, the ZA annual rates from the phase 3 trials were adjusted using data from the placebo arms of two bisphosphonate vs placebo studies in breast and prostate cancer.9,10 The unadjusted rate ratio of SREs in breast cancer (0.59)9 of ZA versus placebo (assumed as the off-therapy SRE)1 and for prostate cancer (0.80 ZA)10 versus placebo (1.49)10 was used as a proxy for all tumors. Calculation was 1 ÷ 0.57 = 1.75 where 0.57 is the weighted average of the relative rates from the two studies.1
Clinical inputs – adverse events, overall survival and treatment discontinuation, by tumor type1
Incorporate annual rate of adverse events (AE)
• The model accounts for the rate (and subsequent costs) of AEs, calculated as the absolute number of AEs ÷ the person time at risk (years) from the combined analysis of three pivotal phase 3 trials, converted to a per-cycle rate
• The following AEs were included in the model: osteonecrosis of the jaw, acute phase reactions, hypocalcemia, renal toxicity
• AEs were not factored as a reason for switching from ZA to XGEVA® in the model, but could lead to treatment discontinuation
Estimate probability of transitioning from “No SRE” and “After First SRE” health states to “Dead” in Markov model
• To obtain cancer-specific survival estimates, survival data pooled across the XGEVA® and ZA treatment arms of the three pivotal phase 3 trials were utilized
• Parametric modeling was applied to estimate survival over the 3-year model horizon. The probability of death changes per cycle as a result of the modeling details
Account for treatment discontinuation
• Treatment discontinuation was incorporated to better reflect the real world. Discontinuation rates per cycle were estimated for each tumor type from the three pivotal phase 3 trials
• For patients who discontinue, the model applies the SRE risk estimates for the “No Treatment” population
Economic inputs
Economic inputs – XGEVA® and ZA acquisition and administration costs1,11-15
*Based on Q3 2017 Center for Medicare and Medicaid Services Average Selling Price (ASP).13 ASP values were estimated based on the ASP payment limit (ASP+6%) for each treatment per mg. ASP+6% was converted to ASP by dividing by 1.06. Per mg ASP rates were multiplied by the prescribed dose per administration. Cost per cycle was adjusted based on proportion of dose received by cancer type from pivotal registrational trial.1
Economic inputs – SRE direct medical costs1
*Value assumed to be across cancer types and SRE type.
Economic inputs – details of direct medical costs1,14-21
*To adjust specific cost sources to a per SRE event, an estimation of the number of SREs annually is required. It was assumed that 70% of patients are treated and 30% are untreated based on an internal analysis of the Flatiron EMR among patients with bone metastases secondary to solid tumors. Using the untreated annual number of SRE events per year of 2.7 when treated with zoledronic acid and 4.7 for untreated patients, the resulting number of SREs per year was estimated as 3.3 (2.7 x 70% + 4.7 x 30%).1
Economic inputs – direct non-medical costs and indirect costs1,2,15,22,23
*Based on assumption of 2 hours driving for SRE visit with a $5 parking fee. Average hourly rates used at a cost of $26.49 obtained from the Bureau of Labor Statistics.15
†Based on a study by Gridelli et al 200722 that evaluated the informal caregiver cost in non-small cell lung cancer (NSCLC) and bone metastases in Italy. The Gridelli et al 2007 study evaluated 104 NSCLC patients in second-line chemotherapy or in supportive therapy who were enrolled in 18 Italian oncology departments and were observed for 3 months. The main caregiver’s workload was assessed monthly by a task scale; other caregivers’ activities were also registered. Formal caregiving time was valued according to market prices; informal caregiving hours were valued using the wage rate for an equivalent service. The distribution of patients in the study included bone/cerebral metastases at 47%, other at 34% and no metastases at 19%. The cost data were adjusted for exchange rate (1.22) and Gross Domestic Product (1.34).1 All values are inflation adjusted from 2004 to March 2017 by multiplying the cost by the Medical Care consumer price index of 1.32.15
‡Based on a study by Qian et al 201523 evaluating the incremental productivity loss from a SRE. Data from patients 18-64 years old with solid tumors and bone metastases, eligible for short-term disability benefits between January 1, 2002 and December 31, 2010, were extracted from MarketScan Research Databases. Short-term disability hours and costs associated with bone metastases and SREs were evaluated. Monthly incremental productivity loss with SRE cost was annualized. Costs were adjusted based on the proportion working, which was assumed to be 35% based on a study by Qian et al 2017 estimating that 65% bone metastases patients were considered elderly.2 Therefore, productivity loss cost was applied to 35% of the patients with SREs. Adjustments were made for the number of SREs per year. To adjust specific cost sources to a per SRE event, an estimation of the number of SREs annually is required. It was assumed that 70% of patients are treated and 30% are untreated based on an internal analysis of the Flatiron EMR among patients with bone metastases secondary to solid tumors. Using the untreated annual number of SRE events per year of 2.7 when treated with zoledronic acid and 4.7 for untreated patients, the resulting number of SREs per year was estimated as 3.3 (2.7 x 70% + 4.7 x 30%). All values are inflation adjusted from 2012 to March 2017 by multiplying the cost by the Medical Care consumer price index of 1.14622.15
Economic inputs – health utility1,24
Estimate and adjust life expectancy to a QALY utilizing health utility values (see details below)
*Value assumed to be the same across cancer types and SRE type.
QALY=quality–adjusted life year.
Important Safety Information
Hypocalcemia
Pre-existing hypocalcemia must be corrected prior to initiating therapy with XGEVA®. XGEVA® can cause severe symptomatic hypocalcemia, and fatal cases have been reported. Monitor calcium levels, especially in the first weeks of initiating therapy, and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when XGEVA® is administered with other drugs that can also lower calcium levels. Advise patients to contact a healthcare professional for symptoms of hypocalcemia.
An increased risk of hypocalcemia has been observed in clinical trials of patients with increasing renal dysfunction, most commonly with severe dysfunction (creatinine clearance less than 30 mL/minute and/or on dialysis), and with inadequate/no calcium supplementation. Monitor calcium levels and calcium and vitamin D intake.
Hypersensitivity
XGEVA® is contraindicated in patients with known clinically significant hypersensitivity to XGEVA®, including anaphylaxis that has been reported with use of XGEVA®. Reactions may include hypotension, dyspnea, upper airway edema, lip swelling, rash, pruritus, and urticaria. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy and discontinue XGEVA® therapy permanently.
Drug Products with Same Active Ingredient
Patients receiving XGEVA® should not take Prolia® (denosumab).
Osteonecrosis of the Jaw
Osteonecrosis of the jaw (ONJ) has been reported in patients receiving XGEVA®, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. In clinical trials in patients with cancer, the incidence of ONJ was higher with longer duration of exposure.
Patients with a history of tooth extraction, poor oral hygiene, or use of a dental appliance are at a greater risk to develop ONJ. Other risk factors for the development of ONJ include immunosuppressive therapy, treatment with angiogenesis inhibitors, systemic corticosteroids, diabetes, and gingival infections.
Perform an oral examination and appropriate preventive dentistry prior to the initiation of XGEVA® and periodically during XGEVA® therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with XGEVA®. Consider temporarily interrupting XGEVA® therapy if an invasive dental procedure must be performed.
Patients who are suspected of having or who develop ONJ while on XGEVA® should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition.
Atypical Subtrochanteric and Diaphyseal Femoral Fracture
Atypical femoral fracture has been reported with XGEVA®. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution.
Atypical femoral fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g. prednisone) at the time of fracture. During XGEVA® treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Any patient who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patients presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of XGEVA® therapy should be considered, pending a risk/benefit assessment, on an individual basis.
Hypercalcemia Following Treatment Discontinuation in Patients with Giant Cell Tumor of Bone (GCTB) and in Patients with Growing Skeletons
Clinically significant hypercalcemia requiring hospitalization and complicated by acute renal injury has been reported in XGEVA®‐treated patients with GCTB and in patients with growing skeletons within one year of treatment discontinuation. Monitor patients for signs and symptoms of hypercalcemia after treatment discontinuation and treat appropriately.
Multiple Vertebral Fractures (MVF) Following Treatment Discontinuation
Multiple vertebral fractures (MVF) have been reported following discontinuation of treatment with denosumab. Patients at higher risk for MVF include those with risk factors for or a history of osteoporosis or prior fractures. When XGEVA® treatment is discontinued, evaluate the individual patient’s risk for vertebral fractures.
Embryo-Fetal Toxicity
XGEVA® can cause fetal harm when administered to a pregnant woman. Based on findings in animals, XGEVA® is expected to result in adverse reproductive effects.
Advise females of reproductive potential to use effective contraception during therapy, and for at least 5 months after the last dose of XGEVA®. Apprise the patient of the potential hazard to a fetus if XGEVA® is used during pregnancy or if the patient becomes pregnant while patients are exposed to XGEVA®.
Adverse Reactions
The most common adverse reactions in patients receiving XGEVA® with bone metastasis from solid tumors were fatigue/asthenia, hypophosphatemia, and nausea. The most common serious adverse reaction was dyspnea. The most common adverse reactions resulting in discontinuation were osteonecrosis and hypocalcemia.
For multiple myeloma patients receiving XGEVA®, the most common adverse reactions were diarrhea, nausea, anemia, back pain, thrombocytopenia, peripheral edema, hypocalcemia, upper respiratory tract infection, rash, and headache. The most common serious adverse reaction was pneumonia. The most common adverse reaction resulting in discontinuation of XGEVA® was osteonecrosis of the jaw.
Indication
XGEVA® is indicated for the prevention of skeletal‐related events in patients with multiple myeloma and in patients with bone metastases from solid tumors.
Please see Full Prescribing Information.
References
- Data on file, Amgen; [XGEVA® First vs ZA Step-Edit Economic Model; 2018].
- Qian Y, Bhowmik D, Kachru N, Hernandez RK. Longitudinal patterns of bone-targeted agent use among patients with solid tumors and bone metastases in the United States. Support Care Cancer. 2017;25:1845-1851.
- Lipton A, Fizazi K, Stopeck AT, et al. Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomized, phase 3 trials. Eur J Cancer. 2012;48:3082-3092.
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- Pavlakis N, Schmidt R, Stockler M. Bisphosphonates for breast cancer. Cochrane Database Syst Rev. 2005;20:CD003474.
- 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.
- XGEVA® (denosumab) prescribing information, Amgen.
- Zoledronic acid prescribing information, Novartis.
- Centers for Medicare & Medicaid Services. 2017 ASP drug pricing files website. https://www.cms.gov/Medicare/Medicare-Fee-for-Service-Part-B-Drugs/McrPartBDrugAvgSalesPrice/2017ASPFiles.html. Accessed November 19, 2018.
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- Bureau of Labor Statistics. CPI-all urban consumers (current series) website. https://data.bls.gov/timeseries/CUUR0000SAM?output_view=pct_12mths. Accessed November 19, 2018.
- Nash Smyth E, Conti I, Wooldridge JE, et al. Frequency of skeletal-related events and associated healthcare resource use and costs in US patients with multiple myeloma. J Med Econ. 2016;19:477-486.
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- Delea T, Langer C, McKiernan J, et al. The cost of treatment of skeletal-related events in patients with bone metastases from lung cancer. Oncology. 2004;67:390-396.
- Xie J, Namjoshi M, Wu EQ, et al. Economic evaluation of denosumab compared with zoledronic acid in hormone-refractory prostate cancer patients with bone metastases. J Manag Care Pharm. 2011;17:621-643.
- Bell MJ, Miller JD, Namjoshi M, et al. Comparative Budget Impact of Formulary Inclusion of Zoledronic Acid and Denosumab for Prevention of Skeletal-Related Events in Patients With Bone Metastases. Poster presented at: ISPOR 16th Annual International Meeting; May 21-25, 2011; Baltimore, Maryland.
- Gridelli C, Ferrara C, Guerriero C, et al. Informal caregiving burden in advanced non-small cell lung cancer: the HABIT study. J Thorac Oncol. 2007;2:475-480.
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