Abstract
Purpose: Targeted therapies, including sunitinib, sorafenib, axitinib, and everolimus, have recently become the mainstay for the treatment of metastatic renal cell carcinoma (mRCC). The objective of this study was to estimate the costs of sequential treatment regimens for mRCC and associated adverse events (AEs) from the Chinese payers’ perspective.
Methods: Key inputs included in the calculation were patient population, dosing information, incidence rates and associated costs of Grade 3/4 AEs, treatment costs (including drug discount programs), and patients’ progression-free survival (PFS) as a proxy for length of treatment. To calculate PFS, this study identified pivotal clinical trials and generated a reconstructed individual patient data set from the published Kaplan-Meier survival curves. The median PFS from the pooled estimates were used in the calculation. In the base-case scenario, sunitinib was used as first line and the other three therapies were used as second line. Sensitivity analyses were conducted where (1) sorafenib was used as first line, or (2) a third-line therapy was added to the base-case scenario.
Results: In the base case, the cost per patient per treatment month (PPPM) cost was the lowest for sunitinib + axitinib among all sequential regimens (¥14,898) and was the highest for sunitinib + sorafenib (¥20,103). If sorafenib is used as first line, everolimus had lower per patient per months (PPPM) cost than axitinib (¥17,046 vs ¥23,337), but also had shorter PFS (13.5 months vs 15 months). Second sensitivity analysis with an additional third-line therapy showed consistent results with the base-case scenario; axitinib as second line was the least costly.
Conclusions: This study demonstrates that, for mRCC sequential treatment, sunitinib followed by axitinib generates the highest cost savings from the Chinese payers’ perspective. Future studies are warranted to examine the cost-effectiveness of various mRCC treatment regimens in Chinese populations.
Introduction
Renal malignancies have been rising in China and worldwideCitation1–3. Renal cell carcinoma (RCC) accounts for ∼90% of those renal malignanciesCitation4–6. The estimated incidence of RCC in China was 3.35 cases per 100,000 in 2011Citation7.
While patients with an early diagnosis of RCC have good prognoses and can be treated with surgery, approximately one-third of patients are diagnosed with RCC after metastasisCitation6,Citation8,Citation9. Patients with metastatic RCC (mRCC) have poor prognoses with a 5-year survival rate of less than 10%, and are highly resistant to chemotherapy and radiotherapyCitation10,Citation11. Therefore, targeted therapies have become the mainstay of mRCC treatment. Currently there are four approved targeted therapies for mRCC treatment in China, including the mammalian target of rapamycin (mTOR) inhibitor everolimus (Novartis Pharmaceuticals Corporation, East Hanover, NJ) and three receptor tyrosine kinase inhibitors (RTKIs): sunitinib (Pfizer Inc., New York, NY), axitinib (Pfizer Inc.), and sorafenib (Bayer HealthCare Pharmaceuticals Inc., Wayne, NJ, and Onyx Pharmaceuticals, Inc, Emeryville, CA)Citation10.
As sequential administration of these targeted therapies improves the duration of progression-free survival (PFS) and overall patient survival, sequential treatment regimens are recommended for mRCCCitation12. The Chinese Society of Clinical Oncology (CSCO) recommends sunitinib and sorafenib as the first-line treatment, axitinib or everolimus for second-line treatment following first-line RTKI or cytokine administration, and finally everolimus or sorafenib as third-line treatment for mRCC.
Although the clinical guidelines recommend sequential treatment, few studies have assessed the total costs associated with sequential treatment regimensCitation12. Previous studies assessed the costs of individual therapies only, and did not evaluate the overall treatment costCitation13–15, which is more reflective of real-world clinical practice. Furthermore, although targeted therapies for mRCC are promising, recent studies suggest that these therapies are associated with adverse events (AEs) such as cardiovascular effects, hypertension, pneumonia, rash, and stomatitisCitation10,Citation16. Such significant side-effects should be considered when evaluating therapy-related costs. The objective of this study was to estimate the costs of treatment and associated AEs for different mRCC sequential treatment regimens from the Chinese payers’ perspective to support informed decision-making. To our knowledge, this study is the first attempt to quantify the overall costs of various sequential treatment regimens for mRCC in China.
Materials and methods
Overview
A cost analysis was performed to assess the healthcare costs of the most common mRCC treatment regimens from the Chinese payer’s perspective. The sequential treatment regimens evaluated in this study are guideline-recommended combinations of the four drugs that are approved for treating mRCC in China (). The base-case scenario evaluated three two-line regimens: sunitinib + axitinib, sunitinib + everolimus, and sunitinib + sorafenib.
Table 1. Evaluated sequential treatment regimens.
Regimens’ total costs were based on treatment costs, which incorporated medication costs and treatment duration, and associated Grade 3/4 AE costs. For treatment duration, patients’ PFS was used as a proxy. Key inputs included in the cost calculation were patient population, dosing information, incidence rates and associated costs of Grade 3/4 AEs, treatment costs (including drug discount programs), and patients’ PFS. The cost analyses were conducted using Microsoft Excel 2007 (Redmond, WA) to ensure both transparency and user-friendliness. All costs are reported in 2016 Chinese Yuan (¥).
Targeted literature review and pooled PFS calculation
Treatment-specific and treatment-line-specific PFS data were used to estimate the duration of each treatment therapy, with an assumption that treatment durations last as long as patients’ PFS. This assumption may over-estimate the treatment duration. However, when treatment duration is unavailable, PFS is often used to replace the missing data, and vice versaCitation17,Citation18. The PFS data were identified from 14 pivotal clinical trials of axitinib, everolimus, sorafenib, and sunitinib in the published literature ()Citation19–32.
Table 2. Pivotal clinical trials included for PFS calculations.
Three studies were excluded from this assessment for the following reasons: cross-over design with unidentified survival duration on one treatmentCitation30, no data reported for each line of therapyCitation31, and no data reported for a Kaplan-Meier curveCitation32.
Given that more than one study reported PFS for second-line everolimus, first-line sorafenib, and first-line sunitinib, we generated a reconstructed individual patient data set for each trial from the published Kaplan-Meier survival curves using the Guyott et al.Citation33 method. These data were then combined to calculate an overall pooled Kaplan-Meier survival curve. The median PFS data from the pooled curves were used in our calculation as the treatment length for these three agents. For others where only a single trial was available, the median PFS was used as the treatment length.
Medication costs and adverse events
Costs of treatment and AEs can be found in . The medication unit costs were retail prices derived from regional medical insurance bureaus representing Beijing and ShanghaiCitation34–36. Patient assistance programs that make drugs more affordable for eligible patients are available in China for sunitinib, axitinib, and sorafenib; Specifically, sunitinib is provided for free after 3 months of treatment, sorafenib after 3 months, and axitinib after 5 months. These programs were incorporated into our calculation. Everolimus did not have an assistance program when we performed this analysis. The calculation also reflected a 50% price discount to axitinib if it is used following sunitinib.
Table 3. Incidence rates and associate costs of grade 3 and 4 adverse events.
For AE costs, incidence rates reported in phase 3 pivotal trials and extracted from each product’s respective package inserts were multiplied by the per-event costs obtained from the literature and local expertsCitation37–43. Inclusion of AEs was based on clinical relevance and cost consideration. Based on inputs from local experts, AEs meeting any of the following criteria were excluded: (1) no treatment for the AE; (2) disease-related rather than treatment-related AE; or (3) if the AE was not mutually exclusive, we excluded the AE with the lower incidence of the two. Due to data availability, AE costs for third-line treatment were assumed to be the same as second-line treatment.
Cost analyses
The cost of each therapy was calculated as the sum of AE costs and medication costs (drug cost plus administration cost) for the treatment duration (). Total treatment regimen costs per patient and costs per patient per treatment month (PPPM) were calculated for each sequential treatment regimen.
Table 4. Medication costs.
Sensitivity analyses
To test the robustness of our results and to reflect other possible scenarios observed in clinical practice, we conducted two scenario analyses: (1) using sorafenib as first line; and (2) adding a third-line therapy. In the first scenario analysis, using sorafenib as first line, we compared costs when using axitinib or everolimus as second line. In the three-line regimen scenario analysis, the first-line therapy was sunitinib, the second line was axitinib or everolimus, and the third line was everolimus or sorafenib ().
Results
PFS calculation
Results of the pooled PFS calculation using the Guyott method for second-line everolimus, first-line sorafenib, and first-line sunitinib are presented in . The overall treatment-line-specific PFS results for all agents indicated that sunitinib and axitinib had longer median PFS (11.0 and 10.1 months, respectively) compared to sorafenib and everolimus (8.3 and 7.9 months, respectively) when used as first-line therapy (). For second-line therapy, median PFS was longest for axitinib (6.7 months) followed by everolimus (4.7 months). Only sorafenib had data available for third-line PFS; third-line PFS was assumed to be the same as second-line PFS for everolimus.
Figure 1. Reconstructed Kaplan-Meier curves from individual published studies.
Table 5. Median (95% CI) progression free survival (in months) used in the cost analysis.
Base-case analysis
In the base-case scenario all patients were treated with sunitinib followed by axinitib, everolimus, or sorafenib. While the sunitinib + axitinib regimen had a slightly higher total cost than sunitinib + everolimus (¥262,957 vs ¥241,489) due to the longer treatment duration (17.7 months vs 16.1 months; , ), sunitinib + axinitib had the lowest PPPM cost (¥14,898) among all sequential regimens. Adverse event costs accounted for 2.6%, 2.7%, and 2.0% of the total costs in the three regimens, respectively. Compared to the sunitinib + sorafenib regimen, overall cost savings of sunitinib + axitinib were ¥51,653 per patient.
Figure 2. Cost per patient per month by treatment line, base-case scenario. Abbreviations, Su, sunitinib; A, axitinib; E, everolimus; S, sorafenib. All costs presented in 2016 ¥.
Figure 3. Cost per patient per month by treatment line: third-line scenario analysis. Abbreviations. Su, sunitinib; A, axitinib; E, everolimus; S, sorafenib. All costs presented in 2016 ¥.
Table 6. Results of base-case scenario.
Scenario sensitivity analysis: sorafenib as first-line therapy
In the scenario analysis using sorafenib as the first-line therapy, patients treated with second-line axitinib were not able to receive the 50% discount on the drug price (as they would have if they received first-line sunitinib). A sequential therapy of sorafenib followed by everolimus resulted in lower PPPM cost (¥17,046) and total cost (¥230,291; ), but PFS was longer among those receiving sorafenib + axitinib (15.0 months vs 13.5 months). Adverse event cost was less than ¥2,000 in both regimens, lower than the base case, driven by the lower AE incidence.
Table 7. Scenario sensitivity analysis: sorafenib as first-line treatment.
Scenario sensitivity analysis: adding third-line therapy
A third-line therapy was added as a sensitivity analysis. The results showed that, regardless of third-line therapy choice, patients receiving second-line axitinib had a lower PPPM cost compared to those receiving second-line everolimus (). Patients treated with the sequential regimen of sunitinib + axitinib + everolimus had the lowest total cost (¥341,824) and PPPM cost (¥14,960; ). Absolute value of the AE cost was higher than the base case (¥7,000) in all regimens, yet accounted for a lower percentage (2%) of the total cost compared to the base-case scenario.
Table 8. Scenario sensitivity analysis: third-line targeted therapy regimens.
Discussion
Although previous studies have assessed the cost of each individual therapy evaluated in this study, there is a lack of data on the cumulative cost of sequential treatment for patients with mRCC. This study is the first to examine the AE costs and total treatment costs of sequential treatment regimens for patients with mRCC from a Chinese payer’s perspective. From clinical trials, we estimated the treatment efficacy for each therapy for a specific treatment line and then calculated the total treatment costs of various sequential treatment regimens. The results indicate that second-line axitinib provides the lowest PPPM costs among first-line sunitinib regimens, regardless of the total number of lines used in the regimen. If sorafenib is used as the first-line therapy, everolimus as the second line provides lower cost than axinitib, but has shorter PFS. The regimen with the lowest PPPM cost is sunitinib + axitinib for a two-line regimen, or sunitinib + axitinib + and everolimus for a three-line regimen. Sunitinib was associated with higher AE cost compared to other agents. Thus, AE cost accounted for a higher percentage of the total regimen cost when sunitinib was used as the first line. However, AE cost accounted for less than 3% in all regimens evaluated. Overall, due to the superior clinical efficacy of axitinib, regimens that include axitinib were associated with the longest PFS and lowest cost compared to other regimens.
To our knowledge, there is no study comparing the cost-effectiveness of sequential treatment regimens of targeted therapies for individuals with mRCC in China. However, a few studies are available outside of China. De Groot et al.Citation44 developed a patient-level simulation model using a Dutch population-based registry to compare the cost-effectiveness of a scenario in which eligible patients received sunitinib followed by a second-line targeted therapy. The authors found that patients not currently on targeted therapy would gain 0.558–0.684 quality-adjusted life-years (QALYs) from sunitinib plus a second-line therapy. Another study evaluated the cost utility of second-line axitinib vs everolimus after sunitinib failure in individuals with mRCC in Portugal. The study found that second-line axitinib increased PFS by 0.2 years and overall survival by 0.5 years, and incremental cost per QALY for axitinib compared to everolimus was €28,598, which is equivalent to ¥246,120Citation45. When second-line axitinib was compared to sorafenib in Cyprus, the probability of being cost-effective at a willingness-to-pay threshold of €100,000 was 70% according to a probabilistic Markov modelCitation15. Finally, a study from a US payer perspective found that axitinib led to greater survival and QALYs, but was not considered cost-effective by the US standard of less than $100,000 per QALYCitation14. As these diverse study results demonstrate, the cost-effectiveness of mRCC therapy in one setting may not be applicable in different settings.
More cost-effectiveness studies are available that compare individual therapies on a specific treatment line. Wu et al.Citation43 analyzed the cost-effectiveness of sunitinib or bevacizumab as first-line compared to traditional cytokine therapy in China, and concluded that traditional cytokine therapy is more cost-effective for most provinces. An abstract compared second-line use of axitinib and everolimus from a Portuguese perspective and suggested that axitinib is cost-saving as a second-line therapyCitation45. However, two other abstracts—one in the UK and one in Colombia—that compared axitinib vs everolimus among patients who failed pazopanib or sunitinib found that everolimus was the dominant optionCitation46,Citation47. It is difficult to deduce the cost-effectiveness of sequential treatment regimens from these studies as conflicting results are reported. Additionally, these studies only consider one line of therapy and do not consider the possible financial impacts of drug discount programs or other options available with sequential treatment. Therefore, the cost-effectiveness of regimens containing targeted therapies remain unclear.
According to clinicians, choosing the line of therapy is mainly based on the clinical guidelines (e.g. CSCO), patient’s disease state (e.g. the pathological type of the tumor), and the efficacy and side-effects of the drugs. In clinical practice, sunitinib is widely used as a first-line therapy in ChinaCitation48. The CSCO guideline for kidney cancer recommends sunitinib as first-line therapy and axitinib as second-line therapy for patients with mRCC who had previously received cytokines or tyrosine kinase inhibitor treatmentsCitation10,Citation49,Citation50. Both everolimus and axitinib demonstrated similar efficacy in the clinical trials and are now considered as category 1 treatments for second-line therapy in China2. In a global, open-label, phase 3 clinical trial, patients in the second-line setting demonstrated a median PFS of 6.7 months (95% CI =6.3–8.6) for axitinib compared with 4.7 months (95% CI =4.6–5.6) for sorafenibCitation20. Several studies in the US also evaluated the efficacy of axitinib vs everolimus using real-world data and found that the two treatments were similar in efficacyCitation51,Citation52. In our economic evaluation, we assigned axitinib a longer treatment duration than everolimus (6.7 months vs 5.2 months) based on pooled clinical trial results and our findings still suggest that using axitinib as second line after sunitinib was associated with greater cost saving than second-line everolimus for treating patients with mRCC.
One important impact factor in our total treatment costs was the patient assistance program scheme or drug price discount that was applied to the study drugs. Patient assistance programs, provided by pharmaceutical manufacturers for expensive innovative medications, have gained popularity in recent years in China. Besides patient assistance programs, which help provide a better estimate of drug costs in the real world, there are more drug price discounts that may be considered. In the regional Catastrophic Disease Insurance reimbursement negotiations, the price for innovative drugs was cut by an average of 10–15%. Since there is no publicly available data on the price discount for mRCC treatment, we did not apply the regional discount, and used the average drug costs extracted from the Ministry of Health and insurance organization databases. Furthermore, in 2016, China initiated a national price negotiation pilot, which aims to reduce all innovative drug prices by halfCitation53. Given such initiatives in China, we expect that the cost of mRCC treatment will decrease over time and the regimen of sunitinib followed by axitinib will have greater cost-saving from the payer’s perspective, as the actual costs paid by the payer would be lower than the inputs used in our analysis.
One of the limitations of the study is that the selected pivotal clinical trials include heterogeneous patient populations, which may affect PFS estimates. We minimized any potential bias due to the heterogeneity by pooling endpoints from multiple clinical trials where appropriate. Next, although Chinese data was used whenever possible, unavailable data input (such as AE rates) were obtained from global clinical trial data. However, since AE costs are minimal, we expect our results to remain unchanged. Finally, this study does not assess the utilities or the cost-effectiveness of the regimens. While the individual drugs’ efficacy and safety have been studied previously, the compound treatment effects and patient utilities for various treatment sequences have not been studied extensively to date. A cost-effectiveness analysis would require a number of significant assumptions, limiting the validity, generalizability, and applicability of such analysis. Therefore, we have conducted a transparent and straightforward cost analysis instead to inform Chinese payers with the total costs of each sequential regimen.
Conclusions
This study demonstrates that, for mRCC sequential treatment, a regimen with first-line sunitinib followed by axitinib generates the highest cost savings from the Chinese payers’ perspective, albeit with higher AE cost compared to first-line soratinib regimens. Future studies are warranted to examine the cost-effectiveness of various mRCC treatment regimens in Chinese populations.
Transparency
Declaration of funding
This study was funded by Pfizer, Inc.
Declaration of financial/other relationships
HR and PD are employees of Pfizer, Inc. SHP, MX, and XG are/were employees of Pharmerit International, which has received consultancy fees from Pfizer, Inc. for this study. GS is an associate director of the Department of Urology at the Fudan University Shanghai Cancer Center and has been an advisor for Pfizer. XL is a surgeon at the Department of Urology at Fudan University Shanghai Cancer Center and has no relationships to declare. JME peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
Author Contributions
All the authors contributed to study design, data analysis and interpretation, and manuscript development.
Ethics statement
All data are from publicly available sources without any approval requirement. According to Chinese regulations, this study does not require any IRB or ethics committee approval.
Acknowledgments
Medical writing assistance was provided by Catherine O’Connor, an employee of Pharmerit International.
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