Advertisement

First-Line Lenvatinib plus Pembrolizumab or Everolimus versus Sunitinib for Advanced Renal Cell Carcinoma: A United States-based Cost-effectiveness Analysis

Running Head: The LP or LE for aRCC
  • Author Footnotes
    ⁎ Contributed equally to this work
    Youwen Zhu
    Footnotes
    ⁎ Contributed equally to this work
    Affiliations
    Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
    Search for articles by this author
  • Author Footnotes
    ⁎ Contributed equally to this work
    Kun Liu
    Footnotes
    ⁎ Contributed equally to this work
    Affiliations
    Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
    Search for articles by this author
  • Libo Peng
    Correspondence
    Correspondence to: Libo Peng, Department of Oncology, Loudi Central Hospital, The Central Hospital of Loudi Affiliated to the University of South China, Loudi, Hunan, 417000, China
    Affiliations
    Department of oncology, Loudi Central Hospital, The Central Hospital of Loudi Affiliated to the University of South China, Loudi, Hunan, 417000, China
    Search for articles by this author
  • Author Footnotes
    ⁎ Contributed equally to this work
Open AccessPublished:November 24, 2022DOI:https://doi.org/10.1016/j.clgc.2022.11.014

      ABSTRACT

      Introduction

      The CLEAR trial indicated that Survival benefits were generated with lenvatinib plus pembrolizumab (LP) or everolimus (LE) than with sunitinib for advanced renal cell carcinoma (aRCC). However, the high cost of immuno-target and dual-targeted treatment, we assessed the cost-effectiveness of lenvatinib plus pembrolizumab or everolimus in the first-line setting for treatment of patients with aRCC from the United States (US) payers’ perspective.

      Methods

      A comprehensive Markov model was developed to evaluate the cost and effectiveness of LP or LE in first-line therapy for aRCC. We estimated life years (LYs), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs). Utility values and direct costs related to the treatments were gathered from the published studies. Then, one-way and probabilistic sensitivity analyses were performed. Additional subgroup analyses were considered.

      Results

      Treatment with LP and LE provided an additional 0.67 QALYs (0.62 LYs) and 0.66 QALYs (0.90 LYs) compared with sunitinib, resulting in ICER of $131,656 per QALY and 201,928 per QALY, respectively. The most influential factor in this model was the cost of pembrolizumab with LP. Probabilistic sensitivity analysis showed there was a 58.97% and 28.91% probability that LP and LE were cost-effective at WTP values of $150,000 per QALY in the US. Subgroup analyses demonstrated that LP was more cost-effective for patients from Western Europe and North America, intermediate risk of the International risk group of Metastatic Renal Cell Carcinoma Database Consortium (IMDC), favorable and intermediate risk group of Memorial Sloan Kettering Cancer Center (MSKCC) and PD-L1 combined positive score greater than or equal to 1%.

      Conclusion

      From the perspective of the US payer, LP is a cost-effective option as first-line treatment for patients with aRCC at a WTP threshold of $150,000 per QALY, but LE is the opposite.

      Key words

      Introduction

      In the United States (US), kidney cancer is the second most common genitourinary cancer, accounting for more than 76,000 new cases and 13,000 deaths in 2021
      • Siegel RL
      • Miller KD
      • Fuchs HE
      • Jemal A.
      Cancer Statistics, 2021.
      . Renal cell carcinoma (RCC) accounts for up to 85% of kidney cancers and about 17% of patients have distant metastatic disease at diagnosis, with a 5-year survival rate of 11.7%
      • Capitanio U
      • Montorsi F.
      Renal cancer.
      ,
      • Perazella MA
      • Dreicer R
      • Rosner MH.
      Renal cell carcinoma for the nephrologist.
      .
      Recently, because of the improvement in survival and quality of life, treatment with immune checkpoint inhibitors (ICIs), either as a dual combination or in combination with vascular epithelial growth factor (VEGF) inhibitors, may replace sunitinib and become a standard modality for advanced renal cell carcinoma (aRCC). Approved treatments in the first-line setting include VEGF inhibitors (lenvatinib, axitinib, sunitinib, pazopanib, cabozantinib) and ICIs (pembrolizumab, nivolumab, ipilimumab).
      Lenvatinib is an oral multikinase inhibitor that targets VEGF. Pembrolizumab is a human immunoglobulin G4 monoclonal antibody that binds to the programmed death 1 receptor. Everolimus is an oral protein kinase inhibitor of the mammalian target of rapamycin (mTOR) serine/threonine kinase signal transduction pathway. The combination regimens of lenvatinib plus pembrolizumab or everolimus showed survival benefits for aRCC according to previous studies
      • Taylor MH
      • Lee CH
      • Makker V
      • et al.
      Phase IB/II Trial of Lenvatinib Plus Pembrolizumab in Patients With Advanced Renal Cell Carcinoma, Endometrial Cancer, and Other Selected Advanced Solid Tumors.
      ,
      • Motzer RJ
      • Hutson TE
      • Glen H
      • et al.
      Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial.
      . In the first-line treatment of patients with aRCC, the CLEAR randomized clinical trial demonstrated that lenvatinib plus pembrolizumab (LP) significantly prolonged overall survival (OS hazard ratio [HR] for death, 0.66; 95% confidence interval [CI], 0.49 to 0.88; p=0.005) and the progression-free survival (PFS 23.9 vs 9.2 months; HR for disease progression or death,0.39; 95% CI, 0.53 to 0.80; p<0.001) than sunitinib. Lenvatinib plus everolimus (LE) also improved the PFS (14.7 vs 9.2 months; HR, 0.65; 95% CI, 0.53 to 0.80; p<0.001), however, no OS benefit was observed (HR for death, 1.15; 95% CI, 0.88 to 1.50; p=0.30). In addition, LP and LE were associated with a higher incidence of grade 3 or higher adverse events than sunitinib (82.4% and 83.1% vs 71.8%)
      • Motzer R
      • Alekseev B
      • Rha SY
      • et al.
      Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma.
      . Subsequently, LP was approved as the first-line treatment for patients with aRCC in all International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic risk by the National Comprehensive Cancer Network (NCCN) in March 2021

      National Comprehensive Cancer Network (NCCN®) clinical practice guidelines in oncology(NCCN® guidelines): Small Cell Lung Cancer (Version.1.2022) https://www.nccn.org.

      .
      Even though the LP treatment is effective and safet in patients with aRCC, there is still a great need of assessing the drug's clinical benefit at a reasonable cost when it is taken into account the high cost of recently approved novel drugs. Therefore, our goal was to evaluate the cost-effectiveness of adopting newer but more costly treatment strategies such as LP as the first-line treatment of aRCC from a US payers’ perspective.

      Methods

      Model structure

      A comprehensive Markov model and decision tree were developed to evaluate the costs and effectiveness of the different first-line treatments of patients with aRCC. The decision trees included three treatments: (1) LP group: lenvatinib plus pembrolizumab; (2) LE group: lenvatinib plus everolimus and (3) sunitinib group. The Markov model included three health states to replace the disease course of aRCC: PFS, progressive disease (PD), and death (eFigure 1 in the supplementary material). All patients started state with PFS and were treated with three treatment strategies until disease progression or intolerable toxicity and adverse effects. Upon PD or severe adverse events (AEs), both patients could receive subsequent treatment until death. Our Markov cycle length in the model was 6 weeks and outcomes were developed over 20 years boundaries given that more than 99% of the cohort died. We adopted the costs and effects of a 3% discount rate per year
      • Goldstein DA
      • Chen Q
      • Ayer T
      • et al.
      First- and second-line bevacizumab in addition to chemotherapy for metastatic colorectal cancer: a United States-based cost-effectiveness analysis.
      . The outputs included the total cost, life-years (LYs), quality-adjusted LYs (QALYs), and incremental cost-effectiveness ratios (ICERs). We also focused on subgroups and conducted a cost-effectiveness analysis. The model structure and data were based on the results of the CLEAR trial
      • Motzer R
      • Alekseev B
      • Rha SY
      • et al.
      Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma.
      and were obtained from US publicly available databases and published literature. The Markov model was using TreeAge Pro 2020 (TreeAge Software, Williamstown, MA, https://www.treeage.com).
      Figure 1
      Figure 1The one-way sensitivity analyses of lenvatinib plus pembrolizumab group (A) and lenvatinib plus everolimus group (B).
      Abbreviation: PFS, progression-free survival; PD, progressive disease; LP, lenvatinib plus pembrolizumab; LE, lenvatinib plus everolimus.

      Model survival and progression risk estimates

      The transition probabilities of death in any state from aRCC for each treatment strategy were estimated based on the OS and PFS curves of the CLEAR trial. We applied the GetData Graph Digitizer (version 2.26; http://www.getdata-graph-digitizer.com/index.php) to collect the data points from the OS and PFS curves and these data points were then used to fit parametric survival models. Parametric models include the Weibull, Exponential, Gompertz, Log-logistic, and Log-normal distributions. According to all aspects, Akaike's information criterion [AIC] and Bayesian information criterion [BIC] are selected to evaluate the fitting degree of the alternative model. Weibull survival curves which were flexible and widely used were matched to the number of patients in the three states over time, as it can monotonically increase or decrease the hazard function, it is suitable for estimating the event that occurs in the early follow-up work period. The survival model selection was shown in previously published research
      • Latimer NR.
      Survival Analysis for Economic Evaluations Alongside Clinical Trials—Extrapolation with Patient-Level Data.
      . A detailed description of the survival model selection was shown in eTable 2 and eFigure 2 in the supplementary material. Then, we used Weibull distribution to operate in R and we got the two-parameter, shape (γ) and scale (λ), which were estimated from this fit and applied to Kaplan-Meier curves using the R (version 4.0.2, http://www.r-project.org) and the method proposed by Hoyle and Henley
      • Hoyle MW
      • Henley W.
      Improved curve fits to summary survival data: application to economic evaluation of health technologies.
      (Table 1).
      Figure 2
      Figure 2The cost-effectiveness acceptability curves.
      Abbreviation: QALY, quality-adjusted life-year.
      Table 1Model parameters: key clinical and health preference data.
      VariableBaseline valueRangeReferenceDistribution
      MinimumMaximum
      Clinical data
      Weibull survival model for OS
      Lenvatinib plus PembrolizumabScale=0.0019236, Shape=1.5242541--
      • Motzer R
      • Alekseev B
      • Rha SY
      • et al.
      Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma.
      ]
      -
      Lenvatinib plus EverolimusScale=0.021345, Shape=0.923460--
      • Motzer R
      • Alekseev B
      • Rha SY
      • et al.
      Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma.
      -
      SunitinibScale=0.021345, Shape=0.903782--
      • Motzer R
      • Alekseev B
      • Rha SY
      • et al.
      Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma.
      -
      Weibull survival model for PFS
      Lenvatinib plus PembrolizumabScale=0.021166, Shape=1.121156--
      • Motzer R
      • Alekseev B
      • Rha SY
      • et al.
      Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma.
      -
      Lenvatinib plus EverolimusScale=0.057445, Shape=0.948028--
      • Motzer R
      • Alekseev B
      • Rha SY
      • et al.
      Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma.
      -
      SunitinibScale=0.090146, Shape=0.917991--
      • Motzer R
      • Alekseev B
      • Rha SY
      • et al.
      Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma.
      -
      Rate of treatment discontinuation
      Lenvatinib plus Pembrolizumab0.600--
      • Motzer R
      • Alekseev B
      • Rha SY
      • et al.
      Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma.
      -
      Lenvatinib plus Everolimus0.686--
      • Motzer R
      • Alekseev B
      • Rha SY
      • et al.
      Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma.
      -
      Sunitinib0.812--
      • Motzer R
      • Alekseev B
      • Rha SY
      • et al.
      Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma.
      -
      Risk for main adverse events in LP group
      Risk of diarrhea0.0970.0780.116
      • Motzer R
      • Alekseev B
      • Rha SY
      • et al.
      Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma.
      Beta
      Risk of hypertension0.2760.2210.331
      • Motzer R
      • Alekseev B
      • Rha SY
      • et al.
      Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma.
      Beta
      Risk of weight decrease0.0800.0640.096
      • Motzer R
      • Alekseev B
      • Rha SY
      • et al.
      Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma.
      Beta
      Risk of proteinuria0.0770.0620.092
      • Motzer R
      • Alekseev B
      • Rha SY
      • et al.
      Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma.
      Beta
      Risk of asthenia0.0540.0430.065
      • Motzer R
      • Alekseev B
      • Rha SY
      • et al.
      Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma.
      Beta
      Risk of lipase increased0.1280.1020.154
      • Motzer R
      • Alekseev B
      • Rha SY
      • et al.
      Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma.
      Beta
      Risk of amylase increased0.0910.0730.109
      • Motzer R
      • Alekseev B
      • Rha SY
      • et al.
      Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma.
      Beta
      Risk for main AEs in LP group
      Risk of diarrhea0.1150.0920.138
      • Motzer R
      • Alekseev B
      • Rha SY
      • et al.
      Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma.
      Beta
      Risk of hypertension0.2250.1800.270
      • Motzer R
      • Alekseev B
      • Rha SY
      • et al.
      Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma.
      Beta
      Risk of decreased appetite0.0620.0500.074
      • Motzer R
      • Alekseev B
      • Rha SY
      • et al.
      Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma.
      Beta
      Risk of fatigue0.0760.0610.091
      • Motzer R
      • Alekseev B
      • Rha SY
      • et al.
      Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma.
      Beta
      Risk of stomatitis0.0620.0500.074
      • Motzer R
      • Alekseev B
      • Rha SY
      • et al.
      Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma.
      Beta
      Risk of weight decrease0.0730.0580.088
      • Motzer R
      • Alekseev B
      • Rha SY
      • et al.
      Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma.
      Beta
      Risk of proteinuria0.0820.0660.098
      • Motzer R
      • Alekseev B
      • Rha SY
      • et al.
      Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma.
      Beta
      Risk of asthenia0.0510.0410.061
      • Motzer R
      • Alekseev B
      • Rha SY
      • et al.
      Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma.
      Beta
      Risk of hypertriglyceridemia0.1130.0900.136
      • Motzer R
      • Alekseev B
      • Rha SY
      • et al.
      Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma.
      Beta
      Risk for main AEs in sunitinib group
      Risk of diarrhea0.0530.1500.226
      • Motzer R
      • Alekseev B
      • Rha SY
      • et al.
      Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma.
      Beta
      Risk of hypertension0.1880.0420.064
      • Motzer R
      • Alekseev B
      • Rha SY
      • et al.
      Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma.
      Beta
      Risk of anemia0.0530.0700.106
      • Motzer R
      • Alekseev B
      • Rha SY
      • et al.
      Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma.
      Beta
      Risk of lipase increased0.0880.0520.078
      • Motzer R
      • Alekseev B
      • Rha SY
      • et al.
      Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma.
      Beta
      Risk of hypertriglyceridemia0.0650.0500.074
      • Motzer R
      • Alekseev B
      • Rha SY
      • et al.
      Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma.
      Beta
      Risk of platelet count decreased0.0620.0450.067
      • Motzer R
      • Alekseev B
      • Rha SY
      • et al.
      Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma.
      Beta
      Risk of thrombocytopenia0.0560.0470.071
      • Motzer R
      • Alekseev B
      • Rha SY
      • et al.
      Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma.
      Beta
      Risk of neutropenia0.0590.0450.067
      • Motzer R
      • Alekseev B
      • Rha SY
      • et al.
      Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma.
      Beta
      Risk of neutrophil count decreased0.0560.1500.226
      • Motzer R
      • Alekseev B
      • Rha SY
      • et al.
      Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma.
      Beta
      Health preference data
      Utility
      Utility PFS in first-line treatment0.760.6080.912
      • de Groot S
      • Redekop WK
      • Versteegh MM
      • et al.
      Health-related quality of life and its determinants in patients with metastatic renal cell carcinoma.
      Beta
      Utility PFS in sunitinib0.730.5840.876
      • Wan X
      • Zhang Y
      • Tan C
      • et al.
      First-line Nivolumab Plus Ipilimumab vs Sunitinib for Metastatic Renal Cell Carcinoma.
      Beta
      Utility PD0.660.5280.792
      • de Groot S
      • Redekop WK
      • Versteegh MM
      • et al.
      Health-related quality of life and its determinants in patients with metastatic renal cell carcinoma.
      Beta
      Disutility due to AEs
      Diarrhea0.0500.0400.060
      • Ding D
      • Hu H
      • Liao M
      • et al.
      Cost-Effectiveness Analysis of Atezolizumab Plus Chemotherapy in the First-Line Treatment of Metastatic Non-Squamous Non-Small Cell Lung Cancer.
      Beta
      Hypertension0.0500.0400.060
      • Wan X
      • Luo X
      • Tan C
      • et al.
      First-line atezolizumab in addition to bevacizumab plus chemotherapy for metastatic, nonsquamous non-small cell lung cancer: A United States-based cost-effectiveness analysis.
      Beta
      Decreased appetite0.2740.2190.329
      • de Groot S
      • Redekop WK
      • Versteegh MM
      • et al.
      Health-related quality of life and its determinants in patients with metastatic renal cell carcinoma.
      Beta
      Fatigue0.7510.6010.901
      • Swinburn P
      • Lloyd A
      • Nathan P
      • et al.
      Elicitation of health state utilities in metastatic renal cell carcinoma.
      Beta
      Anemia0.6760.5410.811
      • Swinburn P
      • Lloyd A
      • Nathan P
      • et al.
      Elicitation of health state utilities in metastatic renal cell carcinoma.
      Beta
      Platelet count decreased0.6500.5200.7
      • Ding D
      • Hu H
      • Liao M
      • et al.
      Cost-Effectiveness Analysis of Atezolizumab Plus Chemotherapy in the First-Line Treatment of Metastatic Non-Squamous Non-Small Cell Lung Cancer.
      Beta
      Thrombocytopenia0.6500.5200.780
      • Ding D
      • Hu H
      • Liao M
      • et al.
      Cost-Effectiveness Analysis of Atezolizumab Plus Chemotherapy in the First-Line Treatment of Metastatic Non-Squamous Non-Small Cell Lung Cancer.
      Beta
      Neutrophil count decreased0.4600.3680.552
      • Wan X
      • Luo X
      • Tan C
      • et al.
      First-line atezolizumab in addition to bevacizumab plus chemotherapy for metastatic, nonsquamous non-small cell lung cancer: A United States-based cost-effectiveness analysis.
      Beta
      Neutropenia0.5000.4000.600
      • Wan X
      • Luo X
      • Tan C
      • et al.
      First-line atezolizumab in addition to bevacizumab plus chemotherapy for metastatic, nonsquamous non-small cell lung cancer: A United States-based cost-effectiveness analysis.
      Beta
      Discount rate0.03--
      • Handorf EA
      • McElligott S
      • Vachani A
      • et al.
      Cost effectiveness of personalized therapy for first-line treatment of stage IV and recurrent incurable adenocarcinoma of the lung.
      -
      Abbreviation: OS, overall survival; PFS, progression-free survival; LP, lenvatinib plus pembrolizumab; LE,lenvatinib plus everolimus; PD, progressive disease; AEs, adverse events.
      The time-dependency transition probabilities(tp) are essential in the model analysis. Tp in each Markov cycle was calculated based on the following formula: The Markov cycle is u and the arrival at state t after u Markov cycles is tu was calculated with the following formula: tp(tu)=1 − exp{λ(t − u)γ − λtγ} (λ > 0, γ > 0)
      • Zeng X
      • Li J
      • Peng L
      • et al.
      Economic outcomes of maintenance gefitinib for locally advanced/metastatic non-small-cell lung cancer with unknown EGFR mutations: a semi-Markov model analysis.

      Utility estimates

      The utility was used to estimate the consumer's quality of life (QoL) and reflected the impacts of the disease-related health state (0 for worst health to 1 for perfect health). We used previously published utilities of 0.76 and 0.66
      • de Groot S
      • Redekop WK
      • Versteegh MM
      • et al.
      Health-related quality of life and its determinants in patients with metastatic renal cell carcinoma.
      as the mean health utility value for the PFS and the PD state, respectively. The utility value of the first-line treatment using sunitinib was 0.73
      • Wan X
      • Zhang Y
      • Tan C
      • et al.
      First-line Nivolumab Plus Ipilimumab vs Sunitinib for Metastatic Renal Cell Carcinoma.
      . We also consider the disutility values of 3/4 adverse events (AEs) in our analysis
      • de Groot S
      • Redekop WK
      • Versteegh MM
      • et al.
      Health-related quality of life and its determinants in patients with metastatic renal cell carcinoma.
      • Wan X
      • Zhang Y
      • Tan C
      • et al.
      First-line Nivolumab Plus Ipilimumab vs Sunitinib for Metastatic Renal Cell Carcinoma.
      • Wan X
      • Luo X
      • Tan C
      • et al.
      First-line atezolizumab in addition to bevacizumab plus chemotherapy for metastatic, nonsquamous non-small cell lung cancer: A United States-based cost-effectiveness analysis.
      • Swinburn P
      • Lloyd A
      • Nathan P
      • et al.
      Elicitation of health state utilities in metastatic renal cell carcinoma.
      • Ding D
      • Hu H
      • Liao M
      • et al.
      Cost-Effectiveness Analysis of Atezolizumab Plus Chemotherapy in the First-Line Treatment of Metastatic Non-Squamous Non-Small Cell Lung Cancer.
      (Table 1).

      Cost inputs

      Direct medical costs included drug costs, AEs costs (assuming that AEs appeared only one model cycle in the PFS and the PD state)
      • Wan X
      • Zhang Y
      • Tan C
      • et al.
      First-line Nivolumab Plus Ipilimumab vs Sunitinib for Metastatic Renal Cell Carcinoma.
      ,
      • Ding D
      • Hu H
      • Shi Y
      • et al.
      Cost-Effectiveness of Pembrolizumab plus Axitinib Versus Sunitinib as First-Line Therapy in Advanced Renal Cell Carcinoma in the U.S.
      ,
      • Perrin A
      • Sherman S
      • Pal S
      • et al.
      Lifetime cost of everolimus vs axitinib in patients with advanced renal cell carcinoma who failed prior sunitinib therapy in the US.
      , administration costs
      • Wan X
      • Zhang Y
      • Tan C
      • et al.
      First-line Nivolumab Plus Ipilimumab vs Sunitinib for Metastatic Renal Cell Carcinoma.
      follow-up, monitoring costs, and terminal care costs
      • Wu B
      • Zhang Q
      • Sun J.
      Cost-effectiveness of nivolumab plus ipilimumab as first-line therapy in advanced renal-cell carcinoma.
      (Table 2).
      Table 2Cost estimates (US $).
      ParametersBaseline valueRangeReferenceDistribution
      MinimumMaximum
      Drug cost, $/per 1 mg
      Lenvatinib12.69310.15415.231]Gamma
      Pembrolizumab51.61641.29361.939
      • Handorf EA
      • McElligott S
      • Vachani A
      • et al.
      Cost effectiveness of personalized therapy for first-line treatment of stage IV and recurrent incurable adenocarcinoma of the lung.
      Gamma
      Everolimus89.59671.677107.515Gamma
      Sunitinib16.90613.52520.288Gamma
      Nivolumab28.48722.79034.184
      • Handorf EA
      • McElligott S
      • Vachani A
      • et al.
      Cost effectiveness of personalized therapy for first-line treatment of stage IV and recurrent incurable adenocarcinoma of the lung.
      Gamma
      Cabozantinib223.820179.056268.584Gamma
      Expenditures on main adverse events, $
      Diarrhea86.35069.080103.62
      • Ding D
      • Hu H
      • Shi Y
      • et al.
      Cost-Effectiveness of Pembrolizumab plus Axitinib Versus Sunitinib as First-Line Therapy in Advanced Renal Cell Carcinoma in the U.S.
      Gamma
      Hypertension63.94051.15276.728
      • Wan X
      • Zhang Y
      • Tan C
      • et al.
      First-line Nivolumab Plus Ipilimumab vs Sunitinib for Metastatic Renal Cell Carcinoma.
      Gamma
      Weight decrease7,439.2105951.3688927.052
      • Perrin A
      • Sherman S
      • Pal S
      • et al.
      Lifetime cost of everolimus vs axitinib in patients with advanced renal cell carcinoma who failed prior sunitinib therapy in the US.
      Gamma
      Proteinuria000
      • Perrin A
      • Sherman S
      • Pal S
      • et al.
      Lifetime cost of everolimus vs axitinib in patients with advanced renal cell carcinoma who failed prior sunitinib therapy in the US.
      Gamma
      Decreased appetite7,064.1705651.3368477.004
      • Perrin A
      • Sherman S
      • Pal S
      • et al.
      Lifetime cost of everolimus vs axitinib in patients with advanced renal cell carcinoma who failed prior sunitinib therapy in the US.
      Gamma
      Fatigue000
      • Wan X
      • Zhang Y
      • Tan C
      • et al.
      First-line Nivolumab Plus Ipilimumab vs Sunitinib for Metastatic Renal Cell Carcinoma.
      Gamma
      Stomatitis121.14096.912145.368
      • Perrin A
      • Sherman S
      • Pal S
      • et al.
      Lifetime cost of everolimus vs axitinib in patients with advanced renal cell carcinoma who failed prior sunitinib therapy in the US.
      Gamma
      Anemia70.52056.41684.624
      • Ding D
      • Hu H
      • Shi Y
      • et al.
      Cost-Effectiveness of Pembrolizumab plus Axitinib Versus Sunitinib as First-Line Therapy in Advanced Renal Cell Carcinoma in the U.S.
      Gamma
      Lipase increased000
      • Perrin A
      • Sherman S
      • Pal S
      • et al.
      Lifetime cost of everolimus vs axitinib in patients with advanced renal cell carcinoma who failed prior sunitinib therapy in the US.
      Gamma
      Amylase increased000
      • Perrin A
      • Sherman S
      • Pal S
      • et al.
      Lifetime cost of everolimus vs axitinib in patients with advanced renal cell carcinoma who failed prior sunitinib therapy in the US.
      Gamma
      Asthenia6,172.4604937.9687406.952
      • Perrin A
      • Sherman S
      • Pal S
      • et al.
      Lifetime cost of everolimus vs axitinib in patients with advanced renal cell carcinoma who failed prior sunitinib therapy in the US.
      Gamma
      Lipase increased000
      • Perrin A
      • Sherman S
      • Pal S
      • et al.
      Lifetime cost of everolimus vs axitinib in patients with advanced renal cell carcinoma who failed prior sunitinib therapy in the US.
      Gamma
      Amylase increased000
      • Perrin A
      • Sherman S
      • Pal S
      • et al.
      Lifetime cost of everolimus vs axitinib in patients with advanced renal cell carcinoma who failed prior sunitinib therapy in the US.
      Gamma
      Hypertriglyceridemia75.33060.26490.396
      • Perrin A
      • Sherman S
      • Pal S
      • et al.
      Lifetime cost of everolimus vs axitinib in patients with advanced renal cell carcinoma who failed prior sunitinib therapy in the US.
      Gamma
      Platelet count decreased9,709.0007767.20011650.800
      • Ding D
      • Hu H
      • Shi Y
      • et al.
      Cost-Effectiveness of Pembrolizumab plus Axitinib Versus Sunitinib as First-Line Therapy in Advanced Renal Cell Carcinoma in the U.S.
      Gamma
      Thrombocytopenia9,709.0007767.20011650.800
      • Ding D
      • Hu H
      • Shi Y
      • et al.
      Cost-Effectiveness of Pembrolizumab plus Axitinib Versus Sunitinib as First-Line Therapy in Advanced Renal Cell Carcinoma in the U.S.
      Gamma
      Neutrophil count decreased36,106.00028884.80043327.200
      • Ding D
      • Hu H
      • Shi Y
      • et al.
      Cost-Effectiveness of Pembrolizumab plus Axitinib Versus Sunitinib as First-Line Therapy in Advanced Renal Cell Carcinoma in the U.S.
      Gamma
      Neutrophil36,106.00028884.80043327.200
      • Ding D
      • Hu H
      • Shi Y
      • et al.
      Cost-Effectiveness of Pembrolizumab plus Axitinib Versus Sunitinib as First-Line Therapy in Advanced Renal Cell Carcinoma in the U.S.
      Gamma
      Follow-up and monitoring per cycle442.3353.8530.8
      • Wu B
      • Zhang Q
      • Sun J.
      Cost-effectiveness of nivolumab plus ipilimumab as first-line therapy in advanced renal-cell carcinoma.
      Gamma
      Administration per cycle144.0115.2172.8
      • Wan X
      • Zhang Y
      • Tan C
      • et al.
      First-line Nivolumab Plus Ipilimumab vs Sunitinib for Metastatic Renal Cell Carcinoma.
      Gamma
      Terminal care per cycle11,2278981.613472.4
      • Perrin A
      • Sherman S
      • Pal S
      • et al.
      Lifetime cost of everolimus vs axitinib in patients with advanced renal cell carcinoma who failed prior sunitinib therapy in the US.
      Gamma
      Based on the CLEAR trial, the patients in the LP group: lenvatinib was administered at a dose of 20 mg orally once daily for each 21day treatment cycle, and pembrolizumab was administered at a dose of 200 mg intravenously on day 1 of each 21day cycle. The patients in the LE group: lenvatinib was administered at a dose of 18 mg and everolimus was administered at a dose of 5 mg orally once daily for each 21-day cycle. The patients in the sunitinib group: sunitinib was administered at a dose of 50 mg orally once daily for 4 weeks of treatment followed by 2 weeks with no treatment. 60% of patients in the LP group, 68.8% of patients in the LE group, and 81.2% of patients in the sunitinib group discontinued study treatment. Then, according to the NCCN guidelines and the CLEAR trial, these patients continued to receive nivolumab and cabozantinib until after death, with each patient receiving terminal care. In the LP, LE, and sunitinib group, 13.6% 51.4%, and 53.1% of patients received nivolumab, respectively; 50.7%, 40.8%, and 41.4% of patients received cabozantinib, respectively.We assumed the patient is 65 years of age, has a weight of 70kg, a height of 70, and a body surface area of 1.84m2
      • Handorf EA
      • McElligott S
      • Vachani A
      • et al.
      Cost effectiveness of personalized therapy for first-line treatment of stage IV and recurrent incurable adenocarcinoma of the lung.
      . The price was derived from the Centers for Medicare & Medicaid Services and the drug price inquiry website (Table 1). The follow-up costs covered fees for computed tomography or magnetic resonance imaging (every 8 weeks from the date of randomization during treatment cycles)
      • Motzer R
      • Alekseev B
      • Rha SY
      • et al.
      Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma.
      . Grade 1/2 events were considered manageable within standard patient monitoring and the correlation with QoL was low
      • de Groot S
      • Redekop WK
      • Versteegh MM
      • et al.
      Health-related quality of life and its determinants in patients with metastatic renal cell carcinoma.
      . Thus, we included only the cost of managing grade 3/4 AEs (a frequency of greater than 5%) in the model, which had notably different probabilities between the arms of the CLEAR trial. AEs costs were derived from previously published studies
      • Wan X
      • Zhang Y
      • Tan C
      • et al.
      First-line Nivolumab Plus Ipilimumab vs Sunitinib for Metastatic Renal Cell Carcinoma.
      ,
      • Ding D
      • Hu H
      • Shi Y
      • et al.
      Cost-Effectiveness of Pembrolizumab plus Axitinib Versus Sunitinib as First-Line Therapy in Advanced Renal Cell Carcinoma in the U.S.
      . All costs associated with healthcare services were inflated to 2021 values according to the US consumer price index. Information on these costs was obtained, shown in Table 2.

      Sensitivity analysis

      We used a series of sensitivity analyses to predict the uncertainty of the model results. One-way sensitivity analysis was conducted within a variance of 20% from their baseline values according to varied values of a certain parameter within its defined range and the established approaches to examine the individual effects of this parameter on the ICERs
      • Goldstein DA
      • Chen Q
      • Ayer T
      • et al.
      First- and second-line bevacizumab in addition to chemotherapy for metastatic colorectal cancer: a United States-based cost-effectiveness analysis.
      ,
      • Zhang Y
      • Baik SH
      • Fendrick AM
      • Baicker K.
      Comparing Local and Regional Variation in Health Care Spending.
      . We also conducted probabilistic sensitivity analyses by performing 10,000 Monte Carlo simulations, and the probabilistic sensitivity analysis was completed to assess the variations in multiple parameters at once
      • Wu B
      • Zhang Q
      • Sun J.
      Cost-effectiveness of nivolumab plus ipilimumab as first-line therapy in advanced renal-cell carcinoma.
      . A cost-effectiveness acceptability curve of each treatment strategy was evaluated as being the most cost-effective at a certain WTP threshold.
      We also considered all patient subgroups of the CLEAR trial. Due to insufficient data for each patient subgroup, we adopted the same baseline sunitinib survival curve for all patients in the sunitinib group, and their LP and LE group survival curves were produced based on the subgroup-specific HRs according to the approach taken by Hoyle et al.
      • Hoyle M
      • Green C
      • Thompson-Coon J
      • et al.
      Cost-Effectiveness of Temsirolimus for First Line Treatment of Advanced Renal Cell Carcinoma.
      for the absence of OS and PFS curves for each patient subgroup.

      Results

      Base case results

      The model projected that the life expectancy of patients receiving LP and LE was 5.98 LYs and 6.26 LYs, which were 0.62 LYs and 0.90 LYs more than those receiving sunitinib, respectively. Accounting for QOL, Patients receiving LP and LE received 4.16 and 4.15 QALYs, which were 0.67 QALYs and 0.66 QALYs more than those receiving sunitinib, respectively. The use of LP and LE cost an additional $88,597 and $132,300, resulting in an ICER of $131,656 and $201,928 per QALY ($144,724 and $147,000 per LY) compared with sunitinib (Table 2).

      Sensitivity analysis

      The one-way sensitivity analyses (Figure 1) indicated that the greatest influence of variables on the ICER in LP compared with sunitinib was the cost of pembrolizumab (ranging from $41.29 to $61.94, with the ICER increasing from -$483.16 per QALY (dominated) to $264,928 per QALY), followed by the utility of PFS, the cost of sunitinib, the cost of lenvatinib. And the results also showed that the greatest influence of variables on the ICER in LE compared with sunitinib was the utility of PFS (ranging from 0.61 to 0.91, with the ICER increasing from $140,956 per QALY to $355,855 per QALY), followed by the cost of everolimus, the cost of sunitinib, the utility of PFS of sunitinib, the cost of lenvatinib.
      The results of probabilistic sensitivity analyses suggested that the probability of LP and LE being cost-effective compared with sunitinib is 58.97% and 28.91% at a willingness-to-pay threshold of $150,000 per QALY. The results of the probabilistic sensitivity analysis were displayed on the ICER scatterplot (eFigure 3 in the supplementary material). The acceptability curve (Figure 2) showed that the probability of LP and LE being cost-effective increases with the increase of WTP compared to sunitinib, and LP is always cost-effective compared to LE regardless of the WTP value.
      The subgroup sensitivity analyses revealed the advantage of LP compared with sunitinib on both the effectiveness and cost in subgroups of Western Europe and North America, intermediate risk group of IMDC, and favorable and intermediate risk group of Memorial Sloan Kettering Cancer Center (MSKCC). In addition, it is worth noting that the ICER for LP compared with sunitinib from $138,093 per QALY for patients with PD-L1 combined positive score greater than or equal to 1% to $177,592 per QALY for patients with PD-L1 combined positive score less than 1%. However, the results of subgroup analyses of LE implied that the ICER for LE compared with sunitinib from $116,963 per QALY for patients with PD-L1 combined positive score less than 1% (Table 3 and eTable 3 in the supplementary material).
      Table 3Baseline results.
      ParametersLenvatinib plus PembrolizumabLenvatinib plus EverolimusSunitinib
      LYs5.986.265.36
      QALYs4.164.153.49
      Total cost $1,120,0201,163,7231,031,423
      ICER $/LY
      Compared to Sunitinib ($/LY).
      144,724147,000-
      ICER $/QALY
      Compared to Sunitinib ($/QALY).
      131,656201,928-
      WTP $/QALY100,000-150,000--
      Abbreviation: ICER, incremental cost-effectiveness ratio; LY, life-year; QALY, quality-adjusted life-year; WTP, willingness-to-pay.
      a Compared to Sunitinib ($/LY).
      b Compared to Sunitinib ($/QALY).

      Discussion

      In recent years, the emergence of combination regimens of ICI plus targeted drugs marked a paradigm shift in the management of patients with aRCC
      • Rassy E
      • Flippot R
      • Albiges L.
      Tyrosine kinase inhibitors and immunotherapy combinations in renal cell carcinoma.
      . Several previous trials showed that first-line immuno-target treatment, such as nivolumab plus cabozantinib, avelumab plus axitinib, and pembrolizumab plus axitinib, achieved survival benefits. Subsequently, many cost-effectiveness analyses have been conducted. According to the data of the JAVELIN Renal 101
      • Motzer RJ
      • Penkov K
      • Haanen J
      • et al.
      Avelumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma.
      trial, Peiyao Lu
      • Lu P
      • Liang W
      • Li J
      • et al.
      A Cost-Effectiveness Analysis: First-Line Avelumab Plus Axitinib Versus Sunitinib for Advanced Renal-Cell Carcinoma.
      indicated avelumab plus axitinib in the first-line treatment was not cost-effective in comparison with sunitinib from the US payer perspective. Based on the data of Keynote-426
      • Powles T
      • Plimack ER
      • Soulières D
      • et al.
      Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial.
      . Our team
      • Ding D
      • Hu H
      • Shi Y
      • et al.
      Cost-Effectiveness of Pembrolizumab plus Axitinib Versus Sunitinib as First-Line Therapy in Advanced Renal Cell Carcinoma in the U.S.
      conducted that pembrolizumab plus axitinib to sunitinib is a cost-effective choice in the first-line treatment of aRCC. Given the positive results of the CLEAR trial recently published, the cost-effectiveness of lenvatinib plus pembrolizumab or everolimus therapy needs to be updated accordingly. We performed the cost-effectiveness analysis of lenvatinib plus pembrolizumab or everolimus versus sunitinib in a first-line setting for patients with aRCC at a WTP threshold of $150,000 per QALY from the perspective of US payers.
      Based on our analysis, LP was cost-effective in the first-line treatment of aRCC at a WTP threshold of $150,000 per QALY with an additional 0.67 QALYs and ICER of $131,656 per QALY versus sunitinib, while LE not was cost-effective with ICER of $201,928 per QALY. On the one hand, it may be due to the high cost of AEs caused by LE, which is $1,336, higher than the cost of AEs caused by LP and the rate of receiving follow-up treatment is higher. On the other hand, the utility of the PFS of LP is much higher than that of LE after the correction of the disutility of AEs. The results of one-way sensitivity analysis in LP compared with sunitinib showed that the cost of pembrolizumab was the most influential factor. The cost of sunitinib and lenvatinib was influential factors in the LE group, and further analysis found that LE was cost-effective when the cost of sunitinib has gone up by 13.1% or the cost of lenvatinib has been reduced by 23.4%. Therefore, changing the price of drugs was an effective and feasible strategy to achieve efficient use of the therapeutic schedule. The results of the probabilistic sensitivity analysis demonstrated that LP and LE would be considered to be cost-effective, compared with that sunitinib, which was 58.97% and 28.91% at a WTP threshold of $150,000 per QALY. Meaningfully, our analysis will be essential to guide policymaking and payment in health care and provide drug pricing decision-makers with the ability to reprice immuno-target treatment. The results of subgroup analyses demonstrated that LP is cost-effective for patients with intermediate-risk group of IMDC, favorable and intermediate risk group of MSKCC and PD-L1 combined positive score greater than or equal to 1%. However, The results of subgroup analyses demonstrated that LE is cost-effective for patients with PD-L1 combined positive score of less than 1%.
      IMDC and MSKCC prognostic models are the current criteria for the stratification of patients with aRCC, which can guide the choice of treatment. Treatment outcomes usually vary by patient risk group, with potentially poorer outcomes for patients with poor risk by IMDC and MSKCC
      • Noe A
      • de Bruijn RE
      • Blank C
      • et al.
      Comparison of pre-treatment MSKCC and IMDC prognostic risk models in patients with synchronous metastatic renal cell carcinoma treated in the era of targeted therapy.
      . According to the IMDC and MSKCC prognostic model and the demographic characteristics of the CLEAR study
      • Motzer R
      • Alekseev B
      • Rha SY
      • et al.
      Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma.
      ,
      • Heng DY
      • Xie W
      • Regan MM
      • et al.
      External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study.
      , more than 50% of patients were classified as intermediate risk, however, more and more evidence shows that the moderate risk group is heterogeneous, which is of great significance for treatment selection, patient consultation and stratification
      • Fay AP
      • Xie WL
      • Lee JL
      • et al.
      Characteristics of long-term and short-term survivors of metastatic renal cell carcinoma treated with targeted therapies: results from the International mRCC Database Consortium.
      • Sella A
      • Michaelson MD
      • Matczak E
      • et al.
      Heterogeneity of Patients With Intermediate-Prognosis Metastatic Renal Cell Carcinoma Treated With Sunitinib.
      • Rini BI
      • Hutson TE
      • Figlin RA
      • et al.
      Sunitinib in Patients With Metastatic Renal Cell Carcinoma: Clinical Outcome According to International Metastatic Renal Cell Carcinoma Database Consortium Risk Group.
      • Iacovelli R
      • De Giorgi U
      • Galli L
      • et al.
      Is It Possible to Improve Prognostic Classification in Patients Affected by Metastatic Renal Cell Carcinoma With an Intermediate or Poor Prognosis?.
      • Fiala O
      • Finek J
      • Poprach A
      • et al.
      Outcomes According to MSKCC Risk Score with Focus on the Intermediate-Risk Group in Metastatic Renal Cell Carcinoma Patients Treated with First-Line Sunitinib: A Retrospective Analysis of 2390 Patients.
      • Savard MF
      • Wells JC
      • Graham J
      • et al.
      Real-World Assessment of Clinical Outcomes Among First-Line Sunitinib Patients with Clear Cell Metastatic Renal Cell Carcinoma (mRCC) by the International mRCC Database Consortium Risk Group.
      . Therefore, it will appear that the result of our subgroup analysis is that the ICER of ICIs combined therapy was a huge discrepancy in each risk group of IMDC and MSKCC.
      Significantly, our subgroup analysis found that treatments of patients with PD-L1 combined positive scores greater than or equal to 1% are cost-effective in the LP group. Several studies have found that PD-L1 expression is predictive of better treatment responses from ICIs in a variety of aRCC
      • Lopez-Beltran A
      • Henriques V
      • Cimadamore A
      • et al.
      The Identification of Immunological Biomarkers in Kidney Cancers.
      ,
      • Rini BI
      • Powles T
      • Atkins MB
      • et al.
      Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial.
      . PD-L1 expression enriched clinical and economic value with ICI monotherapy and ICI doublet in some studies, in which an association between high PD-L1 tumor expression and cost-effectiveness was reported in advanced non-small cell lung cancer treated with pembrolizumab or nivolumab plus ipilimumab
      • She L
      • Hu H
      • Liao M
      • et al.
      Cost-effectiveness analysis of pembrolizumab versus chemotherapy as first-line treatment in locally advanced or metastatic non-small cell lung cancer with PD-L1 tumor proportion score 1% or greater.
      ,
      • Hu H
      • She L
      • Liao M
      • et al.
      Cost-Effectiveness Analysis of Nivolumab Plus Ipilimumab vs. Chemotherapy as First-Line Therapy in Advanced Non-Small Cell Lung Cancer.
      . There's no doubt that the biomarker PD-L1 has been proven to be able to screen out sensitive patients of aRCC with ICIs, but more studies are needed to predict the efficacy and diagnosis of effective molecular markers in the future. While these combination therapies have achieved striking survival benefits, the clinical benefits of personalized treatment for patients are limited. Thus, the ability to identify biomarkers of response to combinations of ICIs and targeted drugs to provide more personalized care and a better choice of therapies for cancer is essential.
      We conclude that LE treatment might not be a cost-effective option for aRCC in the US. Nevertheless, the cost-effectiveness of new cancer treatments, especially those that delay disease progression without changing prognosis, often exceeds the regularly established threshold, supporting the belief that the treatment of metastatic/ advanced cancer may be a higher threshold. However, clinicians’ ethical view is that patients should be provided with the most effective choice regardless of price or cost-effectiveness ratio. The common solution to this situation is to implement a special evaluation proposal plan for anti-tumor treatment, which will implement a tier-based schedule based on the cost-effectiveness of drugs or implement risk sharing plan with manufacturers
      Appraising life-extending, end of life treatments.
      ,
      • Casciano R
      • Chulikavit M
      • Di Lorenzo G
      • et al.
      Economic evaluation of everolimus versus sorafenib for the treatment of metastatic renal cell carcinoma after failure of first-line sunitinib.
      . Therefore, health authorities need to formulate a reasonable cost-effectiveness policy in the oncology field, balancing between financial constraints and patients’ best interests.
      At present, concern about access to, and affordability of, cancer treatment is widespread and shared by the wide clinicians and patients. However, there are high out-of-pocket expenses with minimal effects on cancer innovative treatment, which undermine oncology providers' efforts in providing high-quality and potentially lifesaving cancer care. As our methods of effective cancer therapies continue to expand, incorporating combinations of immunotherapy and targeted or dual-targeted therapies, clinicians must arm themselves with knowledge about the clinical and economic benefits of cancer treatment and address the impact of financial toxicity on our patients
      • Carrera PM
      • Kantarjian HM
      • Blinder VS.
      The financial burden and distress of patients with cancer: Understanding and stepping-up action on the financial toxicity of cancer treatment.
      . Our study provided evidence for American payers to avoid financial toxicity, by suggesting that combinations of immunotherapy and targeted therapies are cost-effective for patients with aRCC.
      There are still some limitations in our study. Firstly, our study is based on the CLEAR trial, the only randomized phase III trial that LP or LE vs sunitinib as first-line therapy for aRCC. Any bias within the trial will be reflected in our study. Second, the long-term efficacy of LP or LE in the model was extrapolated from the clinical data from the CLEAR trial, which is inevitably subject to uncertainty. Third, the CLEAR did not provide the Kaplan-Meier curve for subgroups, making it impossible to run the model completely for each subgroup, and the original group balance produced by randomization may not exist in the subgroups. Thus, the results of the subgroup analyses should be interpreted with caution. Fourth, the costs of grade 1/2 AEs and immune-related AEs were excluded which might overestimate the benefits of LP or LE. Finally, as with most modeling studies, the results are based on data from previously published literature but not collected prospectively. It may not accurately reflect the actual situation of the population in our study.

      Conclusion

      From the perspective of the US payer, we concluded that lenvatinib plus pembrolizumab is cost-effective compared with sunitinib in the first-line setting for treatment of patients with aRCC at a WTP threshold of $150 000 per QALY but LE is the opposite.

      Funding

      Not applicable.

      Consent for publication

      Not applicable.

      Ethics approval and consent to participate

      This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors, it does not require the approval of the independent ethics committee.

      Authors’ contributions

      Y.W.Z., K.L., and L.B.P. performed the experiments. Y.W.Z., and K.L., analyzed the data. L.B.P. contributed analysis tools and funding. Y.W.Z., K.L., and L.B.P. wrote the manuscript. K.L. and Y.W.Z. contributed equally to this article. All authors have read and approved the manuscript.

      Availability of data and materials

      All authors had full access to all of the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis. The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request.

      Author Contributions

      Libo Peng: Conceptualization, Methodology, Software, Resources, Data Curation, Writing-Original Draft, Writing-Review & Editing, Supervision, Project administration, Funding acquisition
      Youwen Zhu: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Writing-Original Draft, Writing-Review & Editing, Visualization
      Kun Liu: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Writing-Original Draft, Writing-Review & Editing
      Libo Peng: Conceptualization, Methodology, Software, Resources, Data Curation, Writing-Original Draft, Writing-Review & Editing, Supervision, Project administration, Funding acquisition. Youwen Zhu: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Writing-Original Draft, Writing-Review & Editing, Visualization. Kun Liu: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Writing-Original Draft, Writing-Review & Editing. Youwen Zhu and Kun Liu contributed equally to this article.

      Clinical Practice Points

      At present, there are various first-line treatment options for advanced renal cell carcinoma. Doctors and patients should consider not only the clinical benefits but also the cost-effectiveness. Therefore, it is necessary to carry out economic assessment
      We evaluated the cost-effectiveness of three strategies for advanced renal cell carcinoma:Lenvatinib plus Pembrolizumab (LP), Lenvatinib plus Everolimus (LE) and Sunitinib
      Our key parameters (survival curve, etc.) were derived from large CLEAR Phase III clinical trials, and Markov model was established to calculate cost total cost of treatment, quality adjusted life years (QALY), incremental cost effectiveness ratio (ICERs).
      The model projected that life Expectancy of patients receiving LP and LE was 5.98 LYs and 6.26 LYs, Which were 0.62 LYs and 0.90 LYs more than those receiving sunitinib, respectively. Accounting for QOL, Receiving LP and LE received 4.16 and 4.15 QALYs, Which were 0.67 QALYs and 0.66 QALYs more than those receiving sunitinib, Respectively. The use of LP and LE cost an additional $88,597 and $132,300, Compared with Sunitinib, $131,656 and $201,928 per QALY ($144,724 and $147,000 per LY)
      Our conclusions provide objective data reference for data when making clinical decisions, Individual treatment of patients, and reference for national health insurance decision-making. (Table 4). eFigure 1. Markov states. eFigure 2. Kaplan-Meier Curve Fitting and Extrapolation. eFigure 3. Probability Sensitivity Analysis Scatter Plot. eTable 1. Drug dose and costs. eTable 2. Summary of statistical goodness-of-fit of K-M curve in the CLEAR trial. eTable 3. Results of subgroup analyses of LE group.
      Table 4Results of subgroup analyses of lenvatinib plus pembrolizumab group.
      SubgroupSimple sizeOS HR (95% CI)PFS HR (95% CI)ICERCost-effectiveness probability at WTP
      LPSunitinib$100,000/QALY$150,000/QALY
      Age
      <65y1942250.63(0.41-0.95)0.37(0.28-0.49)187,84215.89%32.66%
      ≥65y1611320.61(0.40-0.95)0.43(0.31-0.61)166,36819.08%39.52%
      Sex
      Male2552750.70(0.49-0.99)0.38(0.30-0.49)168,32721.59%38.02%
      Female100820.54(0.30-0.94)0.42(0.27-0.66)181,28513.63%35.19%
      Geographic region
      Western Europe and North America1981990.68(0.46-1.00)0.42(0.32-0.57)144,42222.49%51.67%
      Rest of the world1571580.63(0.40-0.99)0.36(0.26-0.49)159,62115.16%46.58%
      MSKCC risk group
      Favorable96970.86(0.38-1.92)0.36(0.23-0.54)94,08349.46%56.89%
      Intermediate2272280.66(0.47-0.94)0.44(0.34-0.58)145,78023.26%42.30%
      Poor32320.50(0.23-1.08)0.18(0.08-0.42)291,0253.18%11.84%
      IMDC risk group
      Favorable1101241.15(0.55-2.40)0.41(0.28-0.62)Dominated
      Subgroup analyses were dominated either due to their lower health benefits and higher costs or because they were not considered cost-effective since the ICER far exceeded the WTP threshold of the US.
      --
      Intermediate2101920.72(0.5-1.05)0.39(0.29-0.52)143,80423.61%51.19%
      Poor33370.30(0.14-0.64)0.28(0.13-0.60)237,9194.65%14.52%
      Baseline Karnofsky performance-status score
      100-902952940.88(0.47-1.67)0.38(0.3-0.48)159,23024.15%40.01%
      80-7060620.56(0.40-0.79)0.44(0.36-0.74)182,44412.08%34.69%
      No. of organs with metastases
      1971080.88(0.47-1.67)0.46(0.30-0.71)Dominated
      Subgroup analyses were dominated either due to their lower health benefits and higher costs or because they were not considered cost-effective since the ICER far exceeded the WTP threshold of the US.
      --
      ≥22542460.56(0.40-0.79)0.46(0.28-0.47)200,71912.31%31.04%
      PD-L1 combined positive score
      ≥ 1%1071190.76(0.46-1.27)0.40(0.27-0.58)138,09324.37%54.59%
      < 1%1121030.50(0.28-0.89)0.39(0.26-0.59)177,59213.87%36.65%
      Abbreviation: LP, Lenvatinib plus Pembrolizumab; CI, confidence interval; ICER, incremental cost-effectiveness ratio; OS HR, overall survival hazard ratio; PFS HR, progression-free survival hazard ratio; WTP, Willingness-to-pay; QALY, quality-adjusted life-year; MSKCC, Memorial Sloan Kettering Cancer Center; IMDC, International Metastatic Renal Cell Carcinoma Database Consortium; PD-L1, programmed cell death-Ligand 1.
      a Subgroup analyses were dominated either due to their lower health benefits and higher costs or because they were not considered cost-effective since the ICER far exceeded the WTP threshold of the US.

      CRediT authorship contribution statement

      Youwen Zhu: Conceptualization, Methodology, Software, Resources, Data curation, Writing – original draft, Writing – review & editing, Supervision, Project administration, Funding acquisition. Kun Liu: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Writing – original draft, Writing – review & editing, Visualization. Libo Peng: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Writing – original draft, Writing – review & editing.

      Competing interests

      All of the authors have indicated that they have no competing interests concerning the content of the article. This manuscript is original and has not been previously published, nor has it been simultaneously submitted to any other journal.

      Acknowledgments

      Not applicable.

      Appendix. Supplementary materials

      References

        • Siegel RL
        • Miller KD
        • Fuchs HE
        • Jemal A.
        Cancer Statistics, 2021.
        CA Cancer J Clin. 2021; 71: 7-33
        • Capitanio U
        • Montorsi F.
        Renal cancer.
        The Lancet. 2016; 387: 894-906
        • Perazella MA
        • Dreicer R
        • Rosner MH.
        Renal cell carcinoma for the nephrologist.
        Kidney Int. 2018; 94: 471-483
        • Taylor MH
        • Lee CH
        • Makker V
        • et al.
        Phase IB/II Trial of Lenvatinib Plus Pembrolizumab in Patients With Advanced Renal Cell Carcinoma, Endometrial Cancer, and Other Selected Advanced Solid Tumors.
        J Clin Oncol. 2020; 38: 1154-1163
        • Motzer RJ
        • Hutson TE
        • Glen H
        • et al.
        Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial.
        Lancet Oncol. 2015; 16: 1473-1482
        • Motzer R
        • Alekseev B
        • Rha SY
        • et al.
        Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma.
        N Engl J Med. 2021;
      1. National Comprehensive Cancer Network (NCCN®) clinical practice guidelines in oncology(NCCN® guidelines): Small Cell Lung Cancer (Version.1.2022) https://www.nccn.org.

        • Goldstein DA
        • Chen Q
        • Ayer T
        • et al.
        First- and second-line bevacizumab in addition to chemotherapy for metastatic colorectal cancer: a United States-based cost-effectiveness analysis.
        J Clin Oncol. 2015; 33: 1112-1118
        • Latimer NR.
        Survival Analysis for Economic Evaluations Alongside Clinical Trials—Extrapolation with Patient-Level Data.
        Medical Decision Making. 2013; 33: 743-754
        • Hoyle MW
        • Henley W.
        Improved curve fits to summary survival data: application to economic evaluation of health technologies.
        BMC Medical Research Methodology. 2011; 11
        • Zeng X
        • Li J
        • Peng L
        • et al.
        Economic outcomes of maintenance gefitinib for locally advanced/metastatic non-small-cell lung cancer with unknown EGFR mutations: a semi-Markov model analysis.
        PLoS One. 2014; 9: e88881
        • de Groot S
        • Redekop WK
        • Versteegh MM
        • et al.
        Health-related quality of life and its determinants in patients with metastatic renal cell carcinoma.
        Qual Life Res. 2018; 27: 115-124
        • Wan X
        • Zhang Y
        • Tan C
        • et al.
        First-line Nivolumab Plus Ipilimumab vs Sunitinib for Metastatic Renal Cell Carcinoma.
        JAMA Oncology. 2019; 5
        • Wan X
        • Luo X
        • Tan C
        • et al.
        First-line atezolizumab in addition to bevacizumab plus chemotherapy for metastatic, nonsquamous non-small cell lung cancer: A United States-based cost-effectiveness analysis.
        Cancer. 2019; 125: 3526-3534
        • Swinburn P
        • Lloyd A
        • Nathan P
        • et al.
        Elicitation of health state utilities in metastatic renal cell carcinoma.
        Curr Med Res Opin. 2010; 26: 1091-1096
        • Ding D
        • Hu H
        • Liao M
        • et al.
        Cost-Effectiveness Analysis of Atezolizumab Plus Chemotherapy in the First-Line Treatment of Metastatic Non-Squamous Non-Small Cell Lung Cancer.
        Adv Ther. 2020; 37: 2116-2126
        • Ding D
        • Hu H
        • Shi Y
        • et al.
        Cost-Effectiveness of Pembrolizumab plus Axitinib Versus Sunitinib as First-Line Therapy in Advanced Renal Cell Carcinoma in the U.S.
        Oncologist. 2020;
        • Perrin A
        • Sherman S
        • Pal S
        • et al.
        Lifetime cost of everolimus vs axitinib in patients with advanced renal cell carcinoma who failed prior sunitinib therapy in the US.
        J Med Econ. 2015; 18: 200-209
        • Wu B
        • Zhang Q
        • Sun J.
        Cost-effectiveness of nivolumab plus ipilimumab as first-line therapy in advanced renal-cell carcinoma.
        Journal for ImmunoTherapy of Cancer. 2018; 6
        • Handorf EA
        • McElligott S
        • Vachani A
        • et al.
        Cost effectiveness of personalized therapy for first-line treatment of stage IV and recurrent incurable adenocarcinoma of the lung.
        J Oncol Pract. 2012; 8: 267-274
      2. https://www.cms.gov/medicare/medicare-part-b-drug-average-sales-price/2021-asp-drug-pricing-files. Accessed April 2021.

      3. https://www.drugs.com/price-guide. Accessed 2021.

        • Zhang Y
        • Baik SH
        • Fendrick AM
        • Baicker K.
        Comparing Local and Regional Variation in Health Care Spending.
        New England Journal of Medicine. 2012; 367: 1724-1731
        • Hoyle M
        • Green C
        • Thompson-Coon J
        • et al.
        Cost-Effectiveness of Temsirolimus for First Line Treatment of Advanced Renal Cell Carcinoma.
        Value in Health. 2010; 13: 61-68
        • Rassy E
        • Flippot R
        • Albiges L.
        Tyrosine kinase inhibitors and immunotherapy combinations in renal cell carcinoma.
        Ther Adv Med Oncol. 2020; 121758835920907504
        • Motzer RJ
        • Penkov K
        • Haanen J
        • et al.
        Avelumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma.
        N Engl J Med. 2019; 380: 1103-1115
        • Lu P
        • Liang W
        • Li J
        • et al.
        A Cost-Effectiveness Analysis: First-Line Avelumab Plus Axitinib Versus Sunitinib for Advanced Renal-Cell Carcinoma.
        Front Pharmacol. 2020; 11: 619
        • Powles T
        • Plimack ER
        • Soulières D
        • et al.
        Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial.
        The Lancet Oncology. 2020; 21: 1563-1573
        • Noe A
        • de Bruijn RE
        • Blank C
        • et al.
        Comparison of pre-treatment MSKCC and IMDC prognostic risk models in patients with synchronous metastatic renal cell carcinoma treated in the era of targeted therapy.
        World J Urol. 2016; 34: 1067-1072
        • Heng DY
        • Xie W
        • Regan MM
        • et al.
        External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study.
        Lancet Oncol. 2013; 14: 141-148
        • Fay AP
        • Xie WL
        • Lee JL
        • et al.
        Characteristics of long-term and short-term survivors of metastatic renal cell carcinoma treated with targeted therapies: results from the International mRCC Database Consortium.
        Clin Genitourin Cancer. 2015; 13: 150-155
        • Sella A
        • Michaelson MD
        • Matczak E
        • et al.
        Heterogeneity of Patients With Intermediate-Prognosis Metastatic Renal Cell Carcinoma Treated With Sunitinib.
        Clin Genitourin Cancer. 2017; 15: 291-299.e291
        • Rini BI
        • Hutson TE
        • Figlin RA
        • et al.
        Sunitinib in Patients With Metastatic Renal Cell Carcinoma: Clinical Outcome According to International Metastatic Renal Cell Carcinoma Database Consortium Risk Group.
        Clin Genitourin Cancer. 2018; 16: 298-304
        • Iacovelli R
        • De Giorgi U
        • Galli L
        • et al.
        Is It Possible to Improve Prognostic Classification in Patients Affected by Metastatic Renal Cell Carcinoma With an Intermediate or Poor Prognosis?.
        Clin Genitourin Cancer. 2018; 16: 355-359.e351
        • Fiala O
        • Finek J
        • Poprach A
        • et al.
        Outcomes According to MSKCC Risk Score with Focus on the Intermediate-Risk Group in Metastatic Renal Cell Carcinoma Patients Treated with First-Line Sunitinib: A Retrospective Analysis of 2390 Patients.
        Cancers (Basel). 2020; 12
        • Savard MF
        • Wells JC
        • Graham J
        • et al.
        Real-World Assessment of Clinical Outcomes Among First-Line Sunitinib Patients with Clear Cell Metastatic Renal Cell Carcinoma (mRCC) by the International mRCC Database Consortium Risk Group.
        Oncologist. 2020; 25: 422-430
        • Lopez-Beltran A
        • Henriques V
        • Cimadamore A
        • et al.
        The Identification of Immunological Biomarkers in Kidney Cancers.
        Front Oncol. 2018; 8: 456
        • Rini BI
        • Powles T
        • Atkins MB
        • et al.
        Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial.
        The Lancet. 2019; 393: 2404-2415
        • She L
        • Hu H
        • Liao M
        • et al.
        Cost-effectiveness analysis of pembrolizumab versus chemotherapy as first-line treatment in locally advanced or metastatic non-small cell lung cancer with PD-L1 tumor proportion score 1% or greater.
        Lung Cancer. 2019; 138: 88-94
        • Hu H
        • She L
        • Liao M
        • et al.
        Cost-Effectiveness Analysis of Nivolumab Plus Ipilimumab vs. Chemotherapy as First-Line Therapy in Advanced Non-Small Cell Lung Cancer.
        Front Oncol. 2020; 10: 1649
      4. Appraising life-extending, end of life treatments.
        National Institute for Health and Clinical Excellence, 2013 (Accessed September 5)
        • Casciano R
        • Chulikavit M
        • Di Lorenzo G
        • et al.
        Economic evaluation of everolimus versus sorafenib for the treatment of metastatic renal cell carcinoma after failure of first-line sunitinib.
        Value Health. 2011; 14: 846-851
        • Carrera PM
        • Kantarjian HM
        • Blinder VS.
        The financial burden and distress of patients with cancer: Understanding and stepping-up action on the financial toxicity of cancer treatment.
        CA Cancer J Clin. 2018; 68: 153-165