Background

Denosumab is being reviewed for the patient population with bone metastases secondary to other solid tumours (OST). A concurrent submission to CDR for patients with bone metastases from breast cancer is currently being reviewed.

Denosumab (Xgeva) is available as a 120 mg/1.7mL single-use vial of solution for injection at a cost of $575.55 per vial (Ontario Drug Benefit Exceptional Access Formulary, October 2015).¹ At the recommended dose of 120 mg/1.7mL every four weeks, the annual cost of denosumab is $7,482.

Denosumab (Xgeva) was reviewed by the Canadian Drug Expert Committee (CDEC) in 2011 and was recommended for prevention of skeletal-related events (SREs) in patients with castrate-resistant prostate cancer with one or more documented bony metastases and good performance status (Eastern Cooperative Oncology Group [ECOG] performance status score of 0 to 2), in jurisdictions listing zoledronic acid for the same indication.²

Approach to This Review

This review was initiated by the Formulary Working Group (FWG) for the drug plans participating in the CADTH Common Drug Review (CDR) program. The manufacturer of denosumab was invited to submit clinical and/or economic information but was not obligated to do so. The manufacturer did not provide an economic model for the population of patients with bone metastases from non–small cell lung cancer (NSCLC) and OST; however, it did provide the report submitted to the National Institute for Health and Care Excellence (NICE) in the UK that included a population with NSCLC and OST.

As no economic information was provided to directly address the cost-effectiveness of denosumab for this indication in Canada, CDR relied on the information available to CDR regarding comparative clinical effectiveness — as assessed by the CDR clinical reviewers — to determine the appropriate type of economic evaluation to address the question of cost-effectiveness (e.g., whether a cost-effectiveness analysis or cost-minimization analysis is warranted). In the absence of the provision of Canadian economic information, CDR also undertook a literature review to appraise the economic literature for the population with OST (including NSCLC) to supplement the clinical and economic evidence provided to CDR.

Cost Comparison

An economic evaluation was not provided in support of this review. The CDR clinical review team, in its assessment of the clinical data for patients with bone metastases secondary to OST, found that denosumab is non-inferior to zoledronic acid in reducing the time to a first SRE, based on the head-to-head phase 3 clinical trial from Other Solid Tumours Study 20050244 (Other Solid Tumours Study 244),^{3, 4} although in a secondary analysis, in which multiple myeloma patients were removed and following adjustment for multiplicity, denosumab was superior to zoledronic acid for the same end point.

The manufacturer supplied CDR with information from an indirect treatment comparison submitted to NICE that includes a comparison of denosumab with zoledronic acid and placebo in the OST population. This same indirect treatment comparison was more comprehensively reported by Ford et al.⁵ The CDR clinical reviewers found the results to be consistent with the conclusion that denosumab is at least as effective as zoledronic acid and superior to placebo for reducing the risk of a first SRE in patients with advanced bone metastases from solid tumours; however, CDR noted substantial uncertainty surrounding the results of the indirect treatment comparison. Further details for the indirect treatment comparison are provided in Appendix 7 of the CDR Clinical Review Report for denosumab. No information (direct head-to-head or otherwise) was provided to CDR to assess the comparison of denosumab versus pamidronate or clodronate for patients with bone metastases secondary to OST.

As a result of the clinical findings, a cost comparison was conducted by CDR from the public health care payer’s perspective to compare the cost of denosumab (subcutaneous injection) with the intravenously infused zoledronic acid (Zometa, generics) and pamidronate (Aredia, generics), and oral clodronate (tablet) (Table 1). Other comparators such as oral bisphosphonates (alendronate/cholecalciferol, alendronate, etidronate, and risedronate) were not considered based on clinical expert opinion. The lower-strength form of zoledronic acid (Aclasta) was not considered as it is not approved for use in patients with bone metastases secondary to OST. The prices of clodronate and denosumab were sourced from the Ontario Drug Benefit Formulary⁶ and Exceptional Access Program¹ respectively, while the prices for zoledronic acid (Zometa) and pamidronate were sourced from the Alberta Blue Cross Formulary⁷ because as of November 2015 neither had prices listed on the Ontario formulary.

Table 1

Cost Comparison Table for Denosumab for the Treatment of Bone Metastases in Patients with Other Solid Tumours.

Summary of the Published Economic Information

CDR undertook a review of the economic literature of denosumab for patients with bone metastases secondary to OST. The literature search was undertaken by an information specialist and identified 150 economic abstracts, of which nine received full text review (Ford et al.,⁵ Yfantopoulos et al.,⁸ Stopeck et al.,⁹ Lothgren et al.,¹⁰ Carter et al.,^{11, 12} Xie et al.,¹³ Snedecor et al.,¹⁴ and Koo et al.¹⁵). Reviews that: did not stratify the population by cancer type or by bisphosphonate; undertook analyses of denosumab versus placebo; presented results for the breast cancer or prostate cancer indications, but not the OST or NSCLC indications; or were reviews of studies that were already captured in the literature search were not included in the review of the literature. The included reports are summarized below, with a more complete review provided in Appendix 3: Review of the Published Literature.

Four economic evaluations of denosumab were identified for patients with bone metastases secondary to OST (not including prostate or breast cancers). Three of the four studies were industry-sponsored — two by Amgen (Stopeck et al.⁹ and Lothgren et al.¹⁰) and one by Novartis (Yfantopoulos et al.⁸) — and one was a study by an independent review group (Ford et al.⁵).

In all of the studies, the primary comparator for denosumab was zoledronic acid. The study by Ford et al.⁵ presented analyses comparing denosumab with best supportive care (BSC) and other bisphosphonates (including pamidronate disodium). One study (Lothgren et al.¹⁰) was a European budget impact assessment based on a patient switching from zoledronic acid to denosumab. The study reported cost savings of between €1,861 and €3,408 with the use of denosumab for patients with OST. The other three studies presented cost-effectiveness analyses of denosumab versus the current standard of therapy. Focusing on the primary comparator of the studies (zoledronic acid), the study results varied substantially. The study by Stopeck et al.⁹ reported higher incremental quality-adjusted life-years (QALYs; 0.06) compared with the studies by Ford et al.⁵ (0.004 to 0.008) and Yfantopoulos et al.⁸ (0.0046 to 0.005). The costed resource items appear to have been similar across the studies (SRE, drug acquisition, drug administration); however, the costs varied substantially between studies, based primarily on the setting. The incremental cost-effectiveness ratios (ICERs) ranged from £5,400 per QALY with a patient access scheme⁵ (PAS) (exchange rate 2010 £ to 2010 C$: £1 = C$1.5918)¹⁶ to €330,000 per QALY⁸ (exchange rate 2012 € to 2012 C$: €1 = C$1.2850).¹⁶ Without the patient access, the ICER was assessed to be greater than £200,000 per QALY⁵ (exchange rate 2010 £ to 2010 C$: £1 = C$1.5918).¹⁶

Common to each of these studies and without a patient access scheme in place, at a willingness to pay of C$50,000 per QALY, denosumab was not cost-effective. A noteworthy observation from the review of published cost-effectiveness analyses for this population is that the findings of the randomized controlled trial (RCT) and network meta-analysis (NMA) indicate small, but non-significant differences between denosumab and zoledronic acid. The results of the published economic evaluation appear to be generally consistent with the CDR analysis: denosumab may be associated with a minimal incremental benefit, while being associated with an incremental treatment cost.

Issues for Consideration

CDR identified the following issues for consideration:

• The appropriate comparator for denosumab differs by jurisdiction based on reimbursed treatments. Different reimbursement policies around the comparators and/or prices will alter the value of the analysis undertaken by CDR.
• Generic forms of pamidronate and zoledronic acid are available in some jurisdictions.
• The funding of infusion costs (related to pamidronate and zoledronic acid in this case) remains uncertain. CDR undertook the base case using the assumption that infusion costs are funded by the manufacturer, while a sensitivity analysis explored the results if the province funded the infusion costs.

Results and Conclusions

Based on the CDR clinical review, the data suggest that denosumab (Xgeva) is at least as effective as zoledronic acid in reducing the time to a first SRE in patients with OST. When considering only drug prices, at the current publicly available prices and recommended doses, the annual cost of denosumab (120 mg every four weeks; $7,482 [Ontario Drug Benefit (OBD) formulary list price]) is more expensive than generic zoledronic acid (4 mg/5mL every three to four weeks; $2,521 to $3,361 annually), and comparable to branded zoledronic acid (Zometa; 4 mg/5mL every three to four weeks; $7,203 to $9,604 annually), based on Alberta Drug Benefit list prices. In a scenario where administration costs were not covered by manufacturers, denosumab (120 mg every four weeks) remained more expensive than generic zoledronic acid (4 mg/5mL every four weeks; $7,513 vs. $5,088 annually).

No clinical comparison of denosumab to pamidronate or clodronate was identified; however, denosumab is more expensive than generic pamidronate (90 mg every three to four weeks; $1,182 to $1,577 [Alberta]), and clodronate (1,600 mg to 2,400 mg daily; $1,764 to $4,288 [ODB]); but comparable to branded pamidronate (90 mg every three to four weeks; $6,510 to $8,680 [Alberta]), Table 1. In a scenario where administration costs were not covered by manufacturers, denosumab (120 mg every four weeks) remained more expensive than generic pamidronate (90 mg every four weeks; $7,513 vs. $4,354 annually), Table 3.

The price of denosumab would need to be reduced to be similar to generic zoledronic acid and generic pamidronate. The extent of the price reduction required will depend on the list prices of comparators (which vary by jurisdiction) and whether manufacturers pay for infusion costs.

Cost Comparison Table

Clinical experts have deemed the comparator treatments presented in Table 1 to be appropriate. Comparators may be recommended (appropriate) practice versus actual practice. Comparators are not restricted to drugs, but may be devices or procedures. Costs are manufacturer list prices, unless otherwise specified. Existing Product Listing Agreements are not reflected in the table and as such may not represent the actual costs to public drug plans.

Note: Denosumab (Prolia) is also available in a 60 mg pre-filled syringe for osteoporosis but is not being considered as part of this review.