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Margetuximab Versus Trastuzumab in Patients With Advanced Breast Cancer: A Cost-effectiveness Analysis

  • Author Footnotes
    # M.F and Y.Y contributed equally.
    Mingyang Feng
    Footnotes
    # M.F and Y.Y contributed equally.
    Affiliations
    Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China

    West China Biomedical Big Data Center, Sichuan University, Chengdu, China
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  • Author Footnotes
    # M.F and Y.Y contributed equally.
    Yang Yang
    Footnotes
    # M.F and Y.Y contributed equally.
    Affiliations
    Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China

    West China Biomedical Big Data Center, Sichuan University, Chengdu, China
    Search for articles by this author
  • Weiting Liao
    Affiliations
    Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China

    West China Biomedical Big Data Center, Sichuan University, Chengdu, China
    Search for articles by this author
  • Qiu Li
    Correspondence
    Address for correspondence: Qiu Li, MD, PhD, Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, No. 37, GuoXue Xiang, Chengdu, 610041, China
    Affiliations
    Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China

    West China Biomedical Big Data Center, Sichuan University, Chengdu, China
    Search for articles by this author
  • Author Footnotes
    # M.F and Y.Y contributed equally.
Open AccessPublished:March 16, 2022DOI:https://doi.org/10.1016/j.clbc.2022.03.002

      Abstract

      Background

      In the international, randomized, open-label, phase III study SOPHIA trial, margetuximab plus chemotherapy showed improved progression-free survival (PFS), and overall survival (OS) compared with trastuzumab plus chemotherapy. This study aimed to investigate whether margetuximab plus chemotherapy is cost-effective compared with trastuzumab plus chemotherapy in pretreated patients with ERBB2-positive advanced breast cancer.

      Materials and Methods

      The clinical data for this model was derived from the SOPHIA trial. Costs and utility were either derived from the standard fee database or extracted from previously published literature. A three-state Markov model was developed to simulate the disease process of patients with advanced breast cancer. One-way sensitivity analyses were conducted to investigate the impact of variables in the analysis model. Probabilistic sensitivity analysis was performed based on 10,000 Monte-Carlo simulations. A subgroup analysis was performed to test whether margetuximab is cost-effective in CD16A-158F allele carriers.

      Results

      Margetuximab plus chemotherapy provided an incremental 0.04 QALYs with an incremental cost of $66,109.78, compared with the trastuzumab plus chemotherapy, resulting in the incremental cost-effectiveness ratio (ICER) of $1,486,442.35/QALY, which exceeded the willingness to pay (WTP) threshold. While in the CD16A-158F allele carriers subgroup, the ICER decreased to $592,669.73/QALY. The variance of the utility of PFS state, costs of margetuximab, and utility of progressive disease state were the most influential factors in the sensitivity analysis.

      Conclusion

      Under current WTP threshold, margetuximab plus chemotherapy is not cost-effective compared with trastuzumab plus chemotherapy in pretreated patients with ERBB2-positive advanced breast cancer. Selecting CD16A-158F allele carriers might be a considerable option to optimize the cost-effectiveness of margetuximab.

      Keywords

      Abbreviations:

      ABC (Advanced breast cancer), PFS (Progression-free survival), OS (Overall survival), PD (Progressive disease)

      Introduction

      Breast cancer is the most common cancer in women, and more than 270,000 new cases of advanced breast cancer (ABC) will be diagnosed in the United States (US) in 2020, and 15% to 20% of them will be human epidermal growth factor receptor 2 (ERBB2, formerly HER2 or HER2/neu) positive.
      • Siegel RL
      • Miller KD
      • Jemal A.
      Cancer statistics, 2020.
      • Choong GM
      • Cullen GD
      • O'Sullivan CC
      Evolving standards of care and new challenges in the management of HER2-positive breast cancer.
      ERBB2, a transmembrane receptor tyrosine kinase in the epidermal growth factor receptor family, is associated with high recurrence rates and inferior survival outcomes.
      • Slamon DJ
      • Godolphin W
      • Jones LA
      • et al.
      Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer.
      ,
      • Piccart-Gebhart MJ
      • Procter M
      • Leyland-Jones B
      • et al.
      Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer.
      In patients with ERBB2-positive ABC, anti-ERBB2 antibodies (such as trastuzumab
      • Slamon DJ
      • Leyland-Jones B
      • Shak S
      • et al.
      Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2.
      and pertuzumab
      • Baselga J
      • Cortés J
      • Kim SB
      • et al.
      Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer.
      ), small-molecule tyrosine kinase inhibitors (lapatinib,
      • Gelmon KA
      • Boyle FM
      • Kaufman B
      • et al.
      Lapatinib or trastuzumab plus taxane therapy for human epidermal growth factor receptor 2-positive advanced breast cancer: final results of NCIC CTG MA.31.
      neratinib
      • Awada A
      • Colomer R
      • Inoue K
      • et al.
      Neratinib plus paclitaxel vs trastuzumab plus paclitaxel in previously untreated metastatic ERBB2-Positive Breast Cancer: the NEfERT-T Randomized Clinical Trial.
      , and tucatinib
      • Murthy RK
      • Loi S
      • Okines A
      • et al.
      Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer.
      ), and antibody-drug conjugate (ADC) (trastuzumab emtansine
      • Verma S
      • Miles D
      • Gianni L
      • et al.
      Trastuzumab emtansine for HER2-positive advanced breast cancer.
      and trastuzumab deruxtecan
      • Modi S
      • Saura C
      • Yamashita T
      • et al.
      Trastuzumab deruxtecan in previously treated HER2-positive breast cancer.
      ) have been approved by the Food and Drug Administration (FDA) and improved these patients’ prognosis.
      Over the past 20 years, major progress has been made in the treatment of patients with ERBB2-positive ABC, however, approximately 20% of patients ultimately die because of primary or acquired resistance to therapy.
      • Vernieri C
      • Milano M
      • Brambilla M
      • et al.
      Resistance mechanisms to anti-HER2 therapies in HER2-positive breast cancer: Current knowledge, new research directions and therapeutic perspectives.
      Therefore, research has focused on strategies to overcome resistance to ERBB2-directed therapies. For patients who had disease progression on two or more prior anti-ERBB2 therapies, margetuximab, a monoclonal antibody that combines trastuzumab with an altered FC-γ domain, leading to the activation of innate and adaptive anti-ERBB2 immune responses, has been reported to be superior effective than trastuzumab in patients with pretreated ERBB2-positive ABC in the SOPHIA trial (ClinicalTrials.gov identifier NCT02492711).
      • Rugo HS
      • Im SA
      • Cardoso F
      • et al.
      Efficacy of Margetuximab vs Trastuzumab in Patients With Pretreated ERBB2-Positive Advanced Breast Cancer: A Phase 3 Randomized Clinical Trial.
      One of the greatest challenges the oncologists facing today is that new therapeutic approaches are frequently associated with higher costs than previous standard techniques and, in some cases, with only marginal improvement in outcomes. To address this question, this cost-effectiveness analysis aimed to compare margetuximab versus trastuzumab in pretreated patients with ABC.

      Materials and Methods

      This analysis used a mathematical modeling approach using inputs from the SOPHIA trial, databases, and academic literature, following Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist.
      • Husereau D
      • Drummond M
      • Petrou S
      • et al.
      Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement.

      Patients and Interventions

      The clinical data of ABC patients was derived from the international, randomized, open-label, phase III study (SOPHIA trial). Eligible patients were ERBB2-positive ABC confirmed by local or optional central testing of the most recent biopsy and must have had progressive disease after 2 or more lines of prior ERBB2-targeted therapy. Then they were randomized (1:1) to margetuximab and trastuzumab to receive cycles of margetuximab intravenously at 15 mg/kg on day 1 of each 21-day cycle, or trastuzumab intravenously at 6 mg/kg on day 1 of each 21-day cycle after a loading dose of 8 mg/kg. Before randomization, investigators would choose one of the following four chemotherapies (capecitabine, eribulin, gemcitabine, or vinorelbine) for each eligible patient. Disease status assessment was performed at baseline, every 6 weeks for the first 24 weeks of therapy, and then every 12 weeks until disease progression.

      Model Construction

      A Markov model was developed with TreeAge Pro 2020 software (TreeAge, Williamstown, MA, USA) to simulate the disease process of patients with ABC. The model structure comprised three mutually exclusive health states: PFS, progressive disease (PD), and death. All of the patients started in the PFS state and the cycle length was one month. Patients either stayed in the initial health status or progressed during each cycle over a lifetime horizon, as shown in Figure 1. To extrapolate the transition probabilities, the original data were extracted from the survival curves in the SOPHIA trial by WebPlotDigitizer (Version:4.4; https://automeris.io/WebPlotDigitizer)
      • Rugo HS
      • Im SA
      • Cardoso F
      • et al.
      Efficacy of Margetuximab vs Trastuzumab in Patients With Pretreated ERBB2-Positive Advanced Breast Cancer: A Phase 3 Randomized Clinical Trial.
      , and these data were then used to fit parametric survival models using the algorithm derived by Hoyle et al.
      • Hoyle MW
      • Henley W.
      Improved curve fits to summary survival data: application to economic evaluation of health technologies.
      Figure 1
      Figure 1Markov model for advanced breast cancer. A Markov model comprising three health states was built.

      Costs

      Costs were estimated from the US-payer's perspective. Costs in this study were derived from Red Book online database (http://www.micromedexsolutions.com, accessed on May 5, 2021) or previously published literature. Only direct medical costs were considered, including targeted drugs’ costs and chemotherapy costs, disease management costs (which included outpatient visit, bone metastases management, hospitalization, monitoring, laboratory scan and tests, bone scan, and CT scan, specified by Mistry et al
      • Mistry R
      • May JR
      • Suri G
      • et al.
      Cost-Effectiveness of Ribociclib plus Letrozole Versus Palbociclib plus Letrozole and Letrozole Monotherapy in the First-Line Treatment of Postmenopausal Women with HR+/HER2- Advanced or Metastatic Breast Cancer: a U.S. payer perspective.
      ), and costs of managing adverse events (AEs) (grade ⩾ 3). For patients in PD state, we assumed they received the best supportive care (BSC) as subsequent therapy. Also, the costs of palliative care and end-of-life costs were taken into consideration.
      • Mistry R
      • May JR
      • Suri G
      • et al.
      Cost-Effectiveness of Ribociclib plus Letrozole Versus Palbociclib plus Letrozole and Letrozole Monotherapy in the First-Line Treatment of Postmenopausal Women with HR+/HER2- Advanced or Metastatic Breast Cancer: a U.S. payer perspective.
      Based on the mean body surface area of 1.71 m2
      • Sacco JJ
      • Botten J
      • Macbeth F
      • Bagust A
      • Clark P.
      The average body surface area of adult cancer patients in the UK: a multicentre retrospective study.
      and a mean bodyweight of 80 Kg,
      • Fryar CD
      • Kruszon-Moran D
      • Gu Q
      • Ogden CL.
      Mean body weight, height, waist circumference, and body mass index among adults: United States, 1999-2000 through 2015-2016.
      the costs for each cycle were calculated. Costs and benefits were discounted to present values at 3% each year. Half-cycle corrections were also applied. All costs were inflated to 2020 using consumer price index (CPI) calculators (available online at: http://www.bls.gov/data/#calculators) which were listed in Table 2. The incremental cost-effectiveness ratio (ICER) was defined as a ratio of incremental costs to incremental benefits.

      Health Outcomes

      In the SOPHIA trial, the median PFS was 5.7 months in the margetuximab cohort, and 4.4 months in the trastuzumab cohort. The median OS of the margetuximab cohort and the trastuzumab cohort was 21.6 and 19.8 months, respectively.
      • Rugo HS
      • Im SA
      • Cardoso F
      • et al.
      Efficacy of Margetuximab vs Trastuzumab in Patients With Pretreated ERBB2-Positive Advanced Breast Cancer: A Phase 3 Randomized Clinical Trial.
      Other clinical efficacy and the proportion of patients with grade 3 to 4 AEs are shown in Table 1.
      Table 1Clinical Efficacy and Proportion of Patients With Grade 3 to 4 Adverse Events
      MargetuximabTrastuzumab
      Clinical efficacy (months)
      Overall population
       Median OS21.619.8
       Median PFS5.74.4
      CD16A-158F carriers
       Median OS23.719.4
       Median PFS6.95.1
      Proportion of patients with grade 3-4 AE
       Fatigue0.050.03
       PPE syndrome<0.010.03
       Neutropenia0.200.12
       Anemia0.050.06
       Neutrophil count decreased0.090.11
       WBC decreased0.020.03
       Febrile neutropenia0.030.05
      AE = adverse event; OS = overall survival; PFS = progression-free survival; PPE = palmar-plantar erythrodysesthesia; WBC = white blood cell.
      Quality-adjusted life-years (QALYs) were estimated for the different treatments. QALYs were calculated as the duration in a health state multiplied by the utility weight of the corresponding health state.
      • Whitehead SJ
      • Ali S.
      Health outcomes in economic evaluation: the QALY and utilities.
      The Euro-Qol 5-dimensional questionnaire (EQ-5D) encompasses a descriptive system of health-related quality of life expressed as utility indexes, ranging from perfect health (1) to death (0).
      • Rabin R
      • de Charro F.
      EQ-5D: a measure of health status from the EuroQol Group.
      The utilities of ABC patients were identified as 0.660 for PFS, 0.447 for PD, and 0 for death according to previously published cost-effectiveness analyses.
      • Pickard AS
      • Neary MP
      • Cella D.
      Estimation of minimally important differences in EQ-5D utility and VAS scores in cancer.
      ,
      • Färkkilä N
      • Torvinen S
      • Roine RP
      • et al.
      Health-related quality of life among breast, prostate, and colorectal cancer patients with end-stage disease.
      ,
      • Paracha N
      • Thuresson PO
      • Moreno SG
      • MacGilchrist KS.
      Health state utility values in locally advanced and metastatic breast cancer by treatment line: a systematic review.

      Sensitivity Analysis

      Input data and ranges in the sensitivity analyses were shown in Table 2. One-way sensitivity analyses were conducted to investigate the impact of variables on the Markov model by varying variables with a range of ±25%, shown in a tornado diagram. Probabilistic sensitivity analysis was conducted using Monte-Carlo simulation of 10,000 patients by simultaneous and random preset variation of parameters to evaluate optimal strategies at different hypothetical willingness-to-pay thresholds (WTP). Cost-effectiveness acceptability curves were developed to reflect the probability that treatment to become cost-effective by varying ceiling ratios.
      • Rabin R
      • de Charro F.
      EQ-5D: a measure of health status from the EuroQol Group.
      A WTP threshold of $100,000 per QALY was applied to the analysis.
      Table 2Input Parameters and Ranges
      MargetuximabTrastuzumabLower ValueUpper ValueDistributionReferences
      Costs($, 2020)
      Costs for PFS per month
       Margetuximab16,000\12,00020,000GammaRed Book
       Trastuzumab

      (Loading dose)
      \10,6678,00013,333GammaRed Book
       Trastuzumab

      (Maintenance dose)
      \8,0006,00010,000GammaRed Book
       Capecitabine1,3331,0001,666GammaRed Book
       Eribulin2,3621,7722,953GammaRed Book
       Gemcitabine9874123GammaRed Book
       Vinorelbine8866110GammaRed Book
      Costs of drug acquisition19,88111,881
       Fatigue (per event)1,0647981,330GammaNiraula, 2013
      • Niraula S
      • Amir E
      • Vera-Badillo F
      • Seruga B
      • Ocana A
      • Tannock IF.
      Risk of incremental toxicities and associated costs of new anticancer drugs: a meta-analysis.
       Neutropenia (per event)4,8273,6206,034GammaZhang, 2019
      • Zhang B
      • Long EF.
      Cost-effectiveness analysis of palbociclib or ribociclib in the treatment of advanced hormone receptor-positive, HER2-negative breast cancer.
       Anemia (per event)13,2459,93416,556GammaLe, 2016
      • Le QA
      • Bae YH
      • Kang JH.
      Cost-effectiveness analysis of trastuzumab emtansine (T-DM1) in human epidermal growth factor receptor 2 (HER2): positive advanced breast cancer.
       Febrile neutropenia (per event)23,52517,64429,406GammaNiraula, 2013
      • Niraula S
      • Amir E
      • Vera-Badillo F
      • Seruga B
      • Ocana A
      • Tannock IF.
      Risk of incremental toxicities and associated costs of new anticancer drugs: a meta-analysis.
       Costs of AE management2,3872,582
       Costs of disease management748561935GammaMistry, 2018
      • Mistry R
      • May JR
      • Suri G
      • et al.
      Cost-Effectiveness of Ribociclib plus Letrozole Versus Palbociclib plus Letrozole and Letrozole Monotherapy in the First-Line Treatment of Postmenopausal Women with HR+/HER2- Advanced or Metastatic Breast Cancer: a U.S. payer perspective.
       Total23,01615,211
      Costs for PD per month
       Costs of disease management1,8281,3712,285GammaMistry, 2018
      • Mistry R
      • May JR
      • Suri G
      • et al.
      Cost-Effectiveness of Ribociclib plus Letrozole Versus Palbociclib plus Letrozole and Letrozole Monotherapy in the First-Line Treatment of Postmenopausal Women with HR+/HER2- Advanced or Metastatic Breast Cancer: a U.S. payer perspective.
       Costs of palliative care4,9233,6926,154GammaMistry, 2018
      • Mistry R
      • May JR
      • Suri G
      • et al.
      Cost-Effectiveness of Ribociclib plus Letrozole Versus Palbociclib plus Letrozole and Letrozole Monotherapy in the First-Line Treatment of Postmenopausal Women with HR+/HER2- Advanced or Metastatic Breast Cancer: a U.S. payer perspective.
       End-of-life cost2,6051,9543,256GammaMistry, 2018
      • Mistry R
      • May JR
      • Suri G
      • et al.
      Cost-Effectiveness of Ribociclib plus Letrozole Versus Palbociclib plus Letrozole and Letrozole Monotherapy in the First-Line Treatment of Postmenopausal Women with HR+/HER2- Advanced or Metastatic Breast Cancer: a U.S. payer perspective.
       Total9,3567,01711,695Gamma
      Transition probabilities
       Overall population
       PPFS-PFS0.8640.820FixedThis study
       PPFS-PD0.1040.146FixedThis study
       PPFS-death0.0320.034FixedThis study
       PPD-PD0.9460.948FixedThis study
       PPD-death0.0540.052FixedThis study
      CD16A-158F Carriers
       PPFS-PFS0.8750.838FixedThis study
       PPFS-PD0.0960.127FixedThis study
       PPFS-death0.0290.035FixedThis study
       PPD-PD0.960.953FixedThis study
       PPD-death0.040.047FixedThis study
      Utilities
       PFS state0.6600.4950.825BetaPickard, 2007
      • Pickard AS
      • Neary MP
      • Cella D.
      Estimation of minimally important differences in EQ-5D utility and VAS scores in cancer.
      & Paracha, 2016
      • Paracha N
      • Thuresson PO
      • Moreno SG
      • MacGilchrist KS.
      Health state utility values in locally advanced and metastatic breast cancer by treatment line: a systematic review.
       PD state0.4470.3350.559BetaFärkkilä, 2014
      • Färkkilä N
      • Torvinen S
      • Roine RP
      • et al.
      Health-related quality of life among breast, prostate, and colorectal cancer patients with end-stage disease.
      & Paracha, 2016
      • Paracha N
      • Thuresson PO
      • Moreno SG
      • MacGilchrist KS.
      Health state utility values in locally advanced and metastatic breast cancer by treatment line: a systematic review.
       Death state0.000Fixed
      Abbreviations: AE = adverse event; P = transition probability; PD = progressive disease; PFS = progression-free survival.

      Subgroup Analysis

      A subgroup cost-effectiveness analysis was performed for CD16A-158F allele carriers, and the transition probabilities were extrapolated using the survival data supplied by the SOPHIA trial. In the CD16A-158F carriers subgroup (n = 437, 86%), the median PFS was 6.9 months in the margetuximab cohort, and 5.1 months in the trastuzumab cohort, and the median OS was 23.7 and 19.4 months in the margetuximab cohort and the trastuzumab cohort, respectively.
      • Rugo HS
      • Im SA
      • Cardoso F
      • et al.
      Efficacy of Margetuximab vs Trastuzumab in Patients With Pretreated ERBB2-Positive Advanced Breast Cancer: A Phase 3 Randomized Clinical Trial.

      Results

      Costs Outcomes

      As for the costs for the PFS state, the costs of drug acquisition accounted most ($19,881 for margetuximab cohort and $11,881 for trastuzumab cohort). The disease management costs were assumed the same in 2 groups. Moreover, the costs related to grade 3 to 4 AEs were $2,387 for the margetuximab cohort and $2,582 for the trastuzumab cohort. As for the costs for PD state, the total cost was $9,356 for both groups, including costs of disease management, palliative care, and end-of-life cost. Overall, the cumulative costs were $279,740.26 for the margetuximab cohort, which was higher than that of $213,630.48 for the trastuzumab cohort (shown in Table 3).
      Table 3Results of the Cost-effectiveness Analysis
      MargetuximabTrastuzumab
      Base-case analysis
      Costs($, 2020)
       Costs for PFS state155,085.2675,951.36
       Costs for PD state124,655.00137,679.12
       Total costs279,740.26213,630.48
       Incremental costs66,109.78
      Effectiveness (QALYs)
       Effectiveness for PFS state0.370.27
       Effectiveness for PD state0.490.54
       Total effectiveness0.860.82
       Incremental effectiveness0.04
      Cost/Effectiveness323,932.60260,811.12
      ICER($ per QALY)1,486,442.35
      Monte Carlo simulation (10000)
      Mean costs($, 2020)279,428.90213,025.18
      SD50,240.6339,212.27
      Mean effectiveness (QALYs)0.860.82
      SD0.150.15
      Abbreviations: PD = progressive disease; PFS = progression-free survival; QALY = quality-adjusted life year; ICER = incremental cost-effectiveness ratio; SD = standard deviation.

      Health Outcomes

      Based on aforementioned algorithm, calibrated transition probabilities were listed in Table 2. The overall QALY in the margetuximab group was higher than that in the trastuzumab (0.86 vs. 0.82 QALYs), as shown in Table 3.

      Base-case Results

      The base-case results of the analysis are presented in Table 3. Treatment with margetuximab was estimated to generate an incremental 0.04 QALYs with incremental costs of $66,109.78 compared with the trastuzumab group, resulting in the ICER of $1,486,442.35/QALY.

      Sensitivity Analysis

      The one-way sensitivity analyses are displayed in the tornado diagram in Figure 2, where the variables were changed across a range of ± 25%. Utility of PFS state, costs of margetuximab, and utility of PD state were the most influential factors in this study. Nevertheless, costs of trastuzumab had important impacts on the outcomes. The result of the Monte-Carlo simulation of 10,000 patients showed that the mean cost and effectiveness gained were: $279,428.9 ± 50,240.63 and 0.86 ± 0.15 QALY for margetuximab cohort, while $213,025.18 ± 39,212.27 and 0.82 ± 0.15 QALY for trastuzumab cohort. The probabilistic sensitivity analysis indicated margetuximab was not likely to be accepted until the WTP rose above $1,500,000 (Figure 3A).
      Figure 2
      Figure 2Tornado diagram. The tornado diagram shows the one-way sensitivity analyses within the appropriate range for each variable. Abbreviations: EV = expected value; ICER = incremental cost-effectiveness ratio; PD = progressive disease; PFS = progression-free survival; QALY = quality-adjusted life year.
      Figure 3
      Figure 3Probabilistic sensitivity analysis. (A) Overall study population. (B) CD16A-158F carriers subgroup. The cost-effectiveness acceptability curve indicates the probability (y-axis) of margetuximab plus chemotherapy being cost-effective compared with trastuzumab plus chemotherapy given the threshold value (x-axis). Abbreviations: CE = cost-effectiveness; QALY = quality-adjusted life year.

      Subgroup Analysis

      In subgroup analyses of CD16A-158F carriers, the cumulative costs and effectiveness were $335,625.74 and 1.06 QALYs for the margetuximab cohort, and $231,381.87 and 0.89 QALYs for the trastuzumab cohort, resulting in the ICER at $592,669.73/QALY. The probabilistic sensitivity analysis indicated margetuximab was more likely to be accepted than trastuzumab when the WTP rose over $600,000 (Figure 3B).

      Discussion

      Based on the phase III SOPHIA trial in patients with pretreated ERBB2-positive ABC, our study indicated margetuximab cost more ($279,740.26 vs. $213,630.48) and yielded more health outcomes than trastuzumab (0.86 vs. 0.82 QALYs), resulting in the ICER of $1,486,442.35/QALY, which much beyond the prespecified WTP threshold ($100,000/QALY), suggesting that margetuximab is not a cost-effective choice compared with trastuzumab. Probabilistic sensitivity analysis suggested this result was robust.
      The most influential factors driving our model are utility of PFS state, costs of margetuximab, and utility of PD state, but the ICER was still higher than WTP threshold no matter how much the variances changed. The results of the sensitivity analysis could be explained by the minor differences of health outcomes predicted by our model between the two groups, as the margetuximab cohort yields only 0.04 QALYs more than the trastuzumab cohort. Moreover, we observed that the costs of margetuximab exerted a significant effect on the sensitivity analysis, so decreasing the price of margetuximab could be a strategy to reduce ICER.
      The SOPHIA trial tested the hypothesis that altering Fc–FcγR interactions can drive clinical benefit in patients with CD16A polymorphisms. They observed that CD16A-158F allele carriers would benefit more from margetuximab because the margetuximab's engineered Fc domain is increased binding to CD16A.
      • Rugo HS
      • Im SA
      • Cardoso F
      • et al.
      Efficacy of Margetuximab vs Trastuzumab in Patients With Pretreated ERBB2-Positive Advanced Breast Cancer: A Phase 3 Randomized Clinical Trial.
      Due to the better clinical effects of the margetuximab observed in the CD16A-158F carriers subgroup, the ICER was decreased to $592,669.73/QALY. In ABC patients received trastuzumab-based therapy, CD16A-158F carriers were observed as lower immune activation,
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      The costs of novel anti-cancer therapies and the economic status of the patients have important impacts on patients’ health outcomes. A large retrospective study
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      • Li Q.
      Cost-Effectiveness of Tucatinib in Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer From the US and Chinese perspectives.
      evaluated tucatinib in ERBB2-positive ABC and concluded that tucatinib combined with trastuzumab and capecitabine is not cost-effective both in US and China, with ICERs at $699,976.43/QALY in the US and $90,585.57/QALY in China, respectively. At the same time, the ICERs in the brain metastasis subgroup decreased to $395,373.81/QALY in the US and $56,403.31/QALY in China, showing a trend to be cost-effective in the ABC patients with brain metastasis. However, another similar study
      • Dong L
      • Lin S
      • Zhong L
      • et al.
      Evaluation of Tucatinib in HER2-positive breast cancer patients with brain metastases: a United States-based cost-effectiveness analysis.
      focused on tucatinib used on ABC patients with brain metastases and still came to the negative conclusion from the US perspective. The cost-effectiveness of trastuzumab emtansine (T-DM1) for patients with ERBB2-positive ABC in China was analyzed in a recently published study
      • Zhang H
      • Zhang Y
      • Huang C
      • Wang J.
      Cost-effectiveness Analysis of Trastuzumab Emtansine as Second-line Therapy for HER2-Positive Breast Cancer in China.
      and T-DM1 is confirmed not a cost-effective option under the current WTP threshold. While a study
      • Diaby V
      • Alqhtani H
      • van Boemmel-Wegmann S
      • et al.
      A cost-effectiveness analysis of trastuzumab-containing treatment sequences for HER-2 positive metastatic breast cancer patients in Taiwan.
      assessed four treatment sequences for HER-2-positive ABC patients and concluded that trastuzumab plus docetaxel as first line followed by T-DM1 and trastuzumab plus lapatinib as second and third line represents the most cost-effective strategy. All of these studies warned us that performing reasonable economic evaluation has become an important and indispensable part of the cancer-treat resources allocation process and could guide clinical practice.
      There exist several limitations in our study. First, the OS data of SOPHIA trial we used was based on the interim analyses conducted after 40% and 70% of target OS events.
      • Rugo HS
      • Im SA
      • Cardoso F
      • et al.
      Efficacy of Margetuximab vs Trastuzumab in Patients With Pretreated ERBB2-Positive Advanced Breast Cancer: A Phase 3 Randomized Clinical Trial.
      Therefore, to simulate the real situation, the proven and reliable method was chosen to extrapolate the transition probabilities. In fact, the final OS result of the SOPHIA trial was reported recently, although not published, and we could anticipate that the margetuximab cohort may even have inferior effectiveness while cost more than trastuzumab cohort (see supplementary materials). Second, due to the SOPHIA trial did not collect quality of life-related information, the utility of disease pattern was extracted from previously published ABC economic model, which may not accurately reflect the patients’ quality of life in the SOPHIA trial, and an updated health quality survey might improve accuracy and robustness. Third, CD16A (FcγRIIIa) genotyping was usually identified by polymerase chain reaction (PCR) amplification.
      • Rugo HS
      • Im SA
      • Cardoso F
      • et al.
      Efficacy of Margetuximab vs Trastuzumab in Patients With Pretreated ERBB2-Positive Advanced Breast Cancer: A Phase 3 Randomized Clinical Trial.
      ,
      • Dall'Ozzo S
      • Andres C
      • Bardos P
      • Watier H
      • Thibault G.
      Rapid single-step FCGR3A genotyping based on SYBR Green I fluorescence in real-time multiplex allele-specific PCR.
      ,
      • Leppers-van de Straat FG
      • van der Pol WL
      • Jansen MD
      • et al.
      A novel PCR-based method for direct Fc gamma receptor IIIa (CD16) allotyping.
      Due to the costs of PCR tests varied a lot between hospitals and institutions, we can't define a very price at this moment. It should be noted that this may be a part of the costs that cannot be ignored in future clinical practice. Last, costs and WTP threshold could vary between different medical centers or different countries, and this may affect the generalizability. Our sensitivity analysis was conducted by varying variables with a range of ± 25%, demonstrating that the results remained robust while variables changed, and a future perspective cost-effectiveness study is expected to further verify our results.
      To our knowledge, this is the first study that evaluates the cost-effectiveness of margetuximab versus trastuzumab in pretreated patients with ABC, indicating that margetuximab is not a cost-effective choice compared with trastuzumab in patients with pretreated ERBB2-positive ABC, which could be considered in the decision-making process to make recommendations regarding the therapy for ABC patients. Selecting CD16A-158F allele carriers, reducing the price of margetuximab, or offering appropriate drug assistance policies might be considerable options to optimize the cost-effectiveness of margetuximab.

      Clinical Practice Points

      In the SOPHIA trial, margetuximab plus chemotherapy showed improved progression-free survival, and overall survival compared with trastuzumab plus chemotherapy.
      In the current cost-effectiveness analysis, treatment with margetuximab was estimated to generate an incremental 0.04 QALYs with incremental costs of $66,109.78 compared with the trastuzumab group, resulting in the ICER of $1,486,442.35/QALY, which beyond the prespecified WTP threshold ($100,000/QALY), suggesting that margetuximab is not a cost-effective choice. In subgroup analyses of CD16A-158F carriers, the ICER reduced to $592,669.73/QALY, showing selecting CD16A-158F allele carriers might be a considerable option to optimize the cost-effectiveness of margetuximab.
      To our best knowledge, this is the first study that evaluates the cost-effectiveness of margetuximab vs. trastuzumab in pretreated patients with ABC. Our study could provide some important information for clinical practice and further studies.

      Author contribution

      All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Mingyang Feng, Yang Yang and Weiting Liao. The first draft of the manuscript was written by Mingyang Feng. The revised draft of the manuscript was written by Mingyang Feng and Yang Yang. All authors read and approved the final manuscript.

      Ethical approval

      This article does not contain any studies with human or animal subjects performed by any of the authors.

      Disclosure

      This work was supported by the 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University (grant No. ZYJC18008 & No. ZYJC18010 ). The funding source was not involved in the study design, data collection, data analysis, data interpretation, the writing of this article or the decision to submit the paper for publication. The authors declare that they have no conflict of interest.

      Appendix. Supplementary materials

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