Article Text

Cost-effectiveness of nivolumab plus ipilimumab as first-line therapy in advanced renal-cell carcinoma
1. Bin Wu1,
2. Qiang Zhang2 and
3. Jie Sun3,c
1. Aff1 0000 0004 0368 8293grid.16821.3cMedical Decision and Economic Group, Department of PharmacySouth Campus, Ren Ji Hospital, School of Medicine, Shanghai Jiaotong University Shanghai China
2. Aff2 0000 0001 2372 7462grid.412540.6Department of Clinical Oncology, Putuo HospitalShanghai University of Traditional Chinese Medicine Shanghai China
3. Aff3 0000 0004 0368 8293grid.16821.3cDepartment of Urology, Ren Ji Hospital, School of MedicineShanghai Jiaotong University Shanghai China
1. c +86-21-68383427 scilwsjtu-sunjie{at}yahoo.com

## Abstract

Background Nivolumab plus ipilimumab improves overall survival and is associated with less toxicity compared with sunitinib in the first-line setting of advanced renal-cell carcinoma (RCC). The current study aimed to assess the cost-effectiveness of nivolumab plus ipilimumab for first-line treatment of advanced RCC from the payer perspectives high- and middle-income regions.

Methods A decision-analytic model was constructed to evaluate the health and economic outcomes of first-line sunitinib and nivolumab plus ipilimumab treatment associated with advanced RCC. The clinical and utility data were obtained from published reports. The cost data were acquired for the payer perspectives of the United States (US), United Kingdom (UK), and China. Sensitivity analyses were performed to test the uncertainties of the results. Quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs) were used.

### Clinical data

Clinical efficacy and safety data were obtained from the CheckMate 214 trial [12]. In intermediate- and poor-risk advanced RCC patients, the 18-month OS rate with nivolumab plus ipilimumab was 75% and was 60% with sunitinib (HR: 0.66, 95% confidence interval [CI]: 0.53–0.82). The median PFS was 11.6 months with nivolumab plus ipilimumab and 8.4 months with sunitinib. According to the results of goodness of fit measured by the R 2 statistic, the Weibull survival function S(t) = exp(−αt β ) and Log-logistic survival function S(t) = 1/(1 + αt β ) were employed for fitting the Kaplan–Meier PFS and OS probabilities of the sunitinib and nivolumab plus ipilimumab strategy, respectively. The estimated parameters of the Weibull survival function and Log-logistic model are shown in Table 1, and calibration curve showed in Additional file 1. The duration of the PFS and PD phases in two competing strategies was calculated using the area under the PFS and OS survival curves. The difference between the OS and PFS estimated from the parametric survival models was used for calculating the probability from PD to death. [18] After the disease progressed, about 66, 15.8 and 33% of patients in the US, UK and China would receive second-line active treatment according to previous reports [1921].

Key clinical and health preference data

### Cost and utility estimates

This analysis adopted the third-party payer, the National Health Service and health care perspectives in the US, UK and China, respectively, which only considered direct medical costs, including the first- and second-line treatment, management of treatment-related serious adverse events (SAEs), routine follow-ups and monitoring, best supportive care (BSC) and terminal care (Table 2). For comparability, costs for three countries were reported in 2017 US dollars. GBP and Chinese Yuan were converted into US dollars by using the following exchange formula: 1US $= GBP 0.7075 and 1US$ = CNY 6.8. US and UK costs associated with health care services were inflated to 2017 values according to the US and UK consumer price index. [22, 23] As previous study done, we therefore adopted the approach of taking the average increase in the index for the previous three years when local index is lack [23]. Because the Chinese health care costs were controlled by the government and kept stable, the Chinese costs were not inflated in the current analysis.

Cost (US $) estimates (expected value [range]) Based on the CheckMate 214 trial, sunitinib was prescribed at a dose of 50 mg/day for 4 weeks followed by 2 weeks off treatment [12]. Nivolumab and ipilimumab were administered intravenously at a dose of 3 mg/kg and 1 mg/kg, respectively, every 3 weeks for four doses (induction phase), followed by nivolumab monotherapy at a dose of 3 mg/kg every 2 weeks (maintenance phase). To calculate the dosage of nivolumab and ipilimumab agents, we assumed a typical patient weighed 71.4 kg in the US, 78.7 kg in the UK and 59 kg in China, and the range (29–112 kg) was used in the sensitivity analysis [16, 24, 25]. Based on previous reports, the maximum treatment duration of nivolumab plus ipilimumab was two years [16, 26]. The medication cost of sunitinib would be adjusted because the actual dosage intensity of sunitinib was 67% of the planned dosage [27]. The prices of sunitinib, nivolumab and ipilimumab in the US (Average Wholesale Price) and UK were collected from public databases and literature, respectively [26, 28]. The Chinese price of nivolumab is$1362/100 mg. Because ipilimumab are still unavailable in the Chinese market, we estimate its price by multiplying the price of ipilimumab in UK and the ratio of the price of nivolumab between UK and China. Other cost data were collected from published literature [19, 21, 23, 24, 26, 2835].

The analysis included grade 3/4 adverse events (AEs) that had notably different probabilities between the arms of the CheckMate 214 trial: fatigue, hypertension, anemia, palmar–plantar erythrodysesthesia and thrombocytopenia [12]. The recommended management of AEs might be found in the clinical guidelines [36, 37]. The costs of managing AE per event in the US, UK and China were extracted from literatures. [19, 21, 3234, 3840]

Mean health utility scores for PFS and PD state were derived from published literature (Table 1) [24, 29, 41, 42]. The disutility values due to grade 1/2 and 3/4 AE were included in this analysis [41].

### Sensitivity analysis

One-way and probabilistic sensitivity analyses were used to test the uncertainty in the model. In the one-way sensitivity analyses, to identify key model input parameters that had substantial impact on the model outcome, relevant parameters were adjusted one-by-one to their respective low and high values, which are listed and illustrated in Tables 1 and 2. The ranges of the parameters used in the one-way sensitivity analyses were obtained from the published literature; when reported data were not available, a range of ±25% of the base-case value was used. An assumed 50% discount of the price of sunitinib, ipilimumab and nivolumab were used for one-way sensitivity analyses. The results of the one-way sensitivity analyses are presented in a Tornado diagram. For the probabilistic sensitivity analyses (PSA), parameters were sampled using the Monte Carlo method to run 1000 replicated outcomes. Based on the ISPOR-SMDM Modeling Good Research Practices Task Force report on model parameter estimation and uncertainty, the values of the input parameters were sampled from lognormal distributions for costs and from β distributions for utility values and probabilities or proportions with an assumed standard deviation of 25% from mean values [43]. The price of sunitinib, ipilimumab and nivolumab were fixed in the PSA due to branded drugs. Cost-effectiveness acceptability curves were generated to present the probabilities of cost-effectiveness.

## Results

### Base-case analysis

For the advanced RCC patients, nivolumab plus ipilimumab instead of sunitinib provided an additional 1.17 life years. Compared with the sunitinib strategy, the mean incremental costs and QALYs of the nivolumab plus ipilimumab were $65,114 and 0.76,$ 94,356 and 0.75 and $3286 and 0.70 for the population in the US, UK and China, respectively. The ICERs for the nivolumab plus ipilimumab versus the sunitinib were$ 85,506 in the US, $126,499 in the UK and$4682 in China (Table 3).

Summary of Cost ($) and Outcome Results in the base-case analysis ### Sensitivity analysis The one-way sensitivity analyses revealed that the results of the model were more sensitive to body weight because this variable had the greatest impact on ICER, which showed that the nivolumab plus ipilimumab strategy would become more favorable as the body weight decreased (Fig. 2). Other considerable influential parameters in the US were the prices of sunitinib and nivolumab, in the UK were the HR of OS for nivolumab plus ipilimumab versus sunitinib, the median OS time of sunitinib treatment and the prices of nivolumab, and in China were the prices of nivolumab, sunitinib and ipilimumab. Model results were robust to changes in other model inputs, including the cost of second-line active treatment, costs and disutilities related to AEs. Fig. 2 One-way sensitivity analyses of nivolumab plus ipilimumab in comparison with sunitinib in United States (a), United Kingdom (b) and China (c) Compared to the sunitinib strategy, the cost-effectiveness acceptability curves showed that the nivolumab plus ipilimumab produced nearly 80.1, 9.2 and 65.2% probabilities of cost-effectiveness when the threshold was equal to$150,000, $65,000 and$27,351 in the US, UK and China, respectively (Fig. 3).

Fig. 3

The cost-effectiveness acceptability curves for nivolumab plus ipilimumab strategy compared to the sunitinib strategy in three countries

## Discussion

Reports of a clinical benefit from nivolumab plus ipilimumab therapy in a clinical study caused great excitement among both oncologists and patients [12]. However, the widespread use of these agents comes with a sharp increase in health resource consumption, which is of concern to clinicians and administrators [44]. This evaluation first investigated the cost-effectiveness of nivolumab plus ipilimumab for patients with newly diagnosed advanced RCC, and our results are of great significance in high- and middle-income settings. The results suggested that the nivolumab plus ipilimumab therapy produced an additional 0.66 life years and > 0.70 QALYs compared with standard sunitinib treatment with a substantial augment of cost, leading to average incremental cost-effectiveness ratios of $85,880/QALY in the US,$126,483/QALY in the UK and $9866 /QALY in China. At a willingness-to-pay threshold values of$150,000, $65,000 and$27,351 per QALY gained in the US, UK and China, this main finding indicated that the nivolumab plus ipilimumab strategy was a cost-effective therapeutic approach in the US and China, but not in the UK. The acceptability curve also demonstrated this finding that a majority of certainty was achieved by nivolumab plus ipilimumab at the threshold of $150,000 in the US and$27,351/QALY in China, and a paucity of certainty at the threshold of $65,000/QALY in UK, respectively. One recent publication reported the results of economic evaluations of nivolumab as second-line therapy for advanced RCC from the payer perspective of the US [16], which presented an ICER of$146,532/QALY versus everolimus that indicated that nivolumab is cost-effective. However, another economic study found that second-line immunotherapy with pembrolizumab versus chemotherapy for bladder cancer is cost-effective in the US, but not in the UK, Canada and Australia. These results are similar to our findings for the US and UK. The potential reason might be the gaps of the prices of sunitinib, nivolumab and ipilimumab between the US and UK. We noted that the price of sunitinib in the US is about four times that in the UK, and nivolumab and ipilimumab are about two times as much. This gap leaded the incremental cost of nivolumab plus ipilimumab against sunitinib to be higher in UK ($94,356) than in US ($ 65,114), which yielded the unfavorable results in UK and favorable results in US. Because the drug prices varied across the different regions due to local affordability and market assess scheme, the economic evaluation needs to consider a diversity of health settings for easy transferability among different regions.

The results of one-way sensitivity analysis found that body weight had the greatest impact on the model outcome. One recent study that evaluated the cost-effectiveness of nivolumab versus everolimus in patients with advanced RCC in the US also found that average body weight had the greatest impact on the ICER for nivolumab versus everolimus (base case US $51,714; range US$8863–\$94,566) [24]. The potential reason for this is that the dosage of sunitinib treatment is administered regardless of body weight, and the dosage of nivolumab and ipilimumab need to be adjusted according to the body weight. More dosages of nivolumab and ipilimumab are needed in patients with high body weight, which might increase barriers to affordability. We suggest that nivolumab and ipilimumab might be paid for per patient or per treatment cycle instead of per vial.

Our analyses have several weaknesses. First, modeling with Weibull and Log-logistic function to project long-term PFS and OS beyond the observational time of the trial is an inevitable limitation of this study. Second, this trial-based study could not wholly track the natural disease course in the real world. This approach could not adequately reflect effectiveness and resource consumption in routine clinical practice. Third, the present study did not solely consider nivolumab monotherapy as second line treatment after the disease progressed because it is only one of alternatives in the subsequently systemic therapy due to their comparable efficacy [4], whose cost also only had a paucity of impact in sensitivity analyses. Fourth, we did not measure the budget impact of nivolumab plus ipilimumab treatment on society. Wide prescription of these agents might intensively raise the financial burden. Fifth, the costs of grade 1/2 AEs were excluded and the impact of immune-related AEs (irAEs) were did not solely considered due to no evidence indicating the notably difference of managing irAEs and non-irAEs, which might underestimate or overestimate the benefits of nivolumab plus ipilimumab. Fortunately, economic outcomes were not sensitive to all parameters related to AEs. Sixth, due to the absence of head-to-head trials, the current analysis did not include other competing agents, such as pazopanib that is a cost-effective option in comparison with sunitinib [27, 35, 41]. The current study needs to be updated by including these novel competing alternatives. Finally, due to the heterogenicity of payer perspectives, such as the mixed public and private payer in the US, the finding should be conservatively generalized to other regions. However, because the findings of this evaluation reflected the general clinical conditions of managing advanced RCC, it might be a valuable reference for decision-makers.

In conclusion, in patients with advanced RCC in the contexts of the US and China, nivolumab plus ipilimumab is likely to be cost-effective in these countries, but not in the UK.

## Acknowledgments

No one need to be acknowledged.

## Authors’ contributions

JS contributed to the conception, design of the primarily model and interpreted the results. BW developed the economic model, performed the analyses and drafted the manuscript. BW and QZ collected and reviewed data. BW, QZ and JS provided clinical input, validated the model assumptions. All authors read and approved the final manuscript.

## Notes

### Ethics approval and consent to participate

This economic analysis was based on a literature review and modeling techniques; this study did not require approval from an Institutional Research Ethics Board.

### Consent for publication

Not applicable.

### Competing interests

None of the authors have anything to declare.

### Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

AEs
BSC
Best supportive care
CTLA-4
cytotoxic T lymphocyte–associated protein 4
FDA
Food and Drug Administration
HR
Hazard ratio
ICERs
Incremental cost-effectiveness ratios
mTOR
Mammalian target of rapamycin
PD
Progressed disease
PD-1
Programmed cell death 1
PSA
Probabilistic sensitivity analyses
QALYs
RCC
Renal-cell carcinoma
SAEs
UK
United Kingdom
US
United States
VEGFR
Vascular endothelial growth factor receptor

1. 1.
2. 2.
3. 3.
4. 4.
5. 5.
6. 6.
7. 7.
8. 8.
9. 9.
10. 10.
11. 11.
12. 12.
13. 13.
14. 14.
15. 15.
16. 16.
17. 17.
18. 18.
19. 19.
20. 20.
21. 21.
22. 22.
23. 23.
24. 24.
25. 25.
26. 26.
27. 27.
28. 28.
29. 29.
30. 30.
31. 31.
32. 32.
33. 33.
34. 34.
35. 35.
36. 36.
37. 37.
38. 38.
39. 39.
40. 40.
41. 41.
42. 42.
43. 43.
44. 44.
45. 45.

## Footnotes

• Funding This study was supported by the Fourth Round of the Three-year Action Plan on Public Health Discipline and Talent Program (Evidence-based Public Health and Health Economics, No. 15GWZK0901) from the Shanghai Health Commission.

• Availability of data and materials No additional data are available.

• Electronic supplementary material The online version of this article (10.1186/s40425-018-0440-9) contains supplementary material, which is available to authorized users.